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Various AAV Serotypes and Their Applications in Gene Therapy: An Overview

Shaza S. Issa, Alisa A. Shaimardanova, Valeriya V. Solovyeva and 1 more

Cells · 2023 · Review · CC BY

doi:10.3390/cells12050785

Abstract

Despite scientific discoveries in the field of gene and cell therapy, some diseases still have no effective treatment. Advances in genetic engineering methods have enabled the development of effective gene therapy methods for various diseases based on adeno-associated viruses (AAVs). Today, many AAV-based gene therapy medications are being investigated in preclinical and clinical trials, and new ones are appearing on the market. In this article, we present a review of AAV discovery, properties, different serotypes, and tropism, and a following detailed explanation of their uses in gene therapy for disease of different organs and systems.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 18, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Thanks to the rapid progress in biomedical technologies, large developments of novel high-tech treatment approaches have become possible today for several human diseases. However, despite scientific discoveries in the field of gene and cell therapy, some diseases still have no effective treatment. Advances in genetic engineering methods have enabled the development of effective gene therapy methods for various diseases based on adeno-associated viruses (AAVs). AAVs are effectively used to treat a number of genetic and acquired human diseases, more specifically, monogenic hereditary ones, i.e., diseases caused by mutations in one gene. Today, many AAV-based gene therapy medications are being investigated in preclinical and clinical trials, and new ones are appearing on the market for the treatment of numerous human diseases, including those that were previously considered incurable.

To date, there are only a few approved AAV-based gene therapy medications. For example, the US Food and Drug Administration (FDA) recently approved “Hemgenix”, a drug for the treatment of hemophilia type B, which is caused by congenital deficiency of factor IX. The drug is an AAV serotype 5 (AAV5), carrying the gene of deficient factor IX. As for hemophilia type A, Roctavian has also recently been approved by the FDA as an AAV5-based gene therapy vector, carrying the deficient factor VIII gene, driven by a liver-selective promoter. Another breakthrough gene therapy medication is “Zolgensma”, which was intended for spinal muscular atrophy (SMA) treatment, a disease characterized by degeneration of the anterior horns motor neurons in the spinal cord resulting in a loss of their functions. Zolgensma is an AAV-serotype-9 (AAV9)-based vector encoding complementary DNA (cDNA) of the survival motor neuron 1 gene (survival motor neuron, SMN1). The drug was approved by the FDA in May 2019 for the treatment of type 1 SMA. Following intravenous administration, AAV9 crosses the blood–brain barrier (BBB) and provides targeted delivery of the SMN gene to neurons. It has been shown that intravenous administration of Zolgensma leads to an improvement in patients’ motor skills, along with a decrease in the clinical manifestations of SMA. Another FDA-approved AAV-based gene therapy medication is Luxturna, which is intended for the treatment of retinal dystrophy caused by biallelic mutations in the RPE65 gene (an enzyme of retinal cells involved in light-sensitive pigment regeneration). Drug delivery to the retinal cells leads to synthesis restoration of normal RPE65 protein, which is necessary for the regeneration of the photosensitive pigment. The very first AAV-based gene therapy medication to be registered is Glybera, which was approved by the European Commission for the treatment of a rare hereditary disease, lipoprotein lipase deficiency.

Nevertheless, despite the successful development of AAV-based gene therapy medications, many preclinical and clinical studies still get suspended or terminated, without resulting in a drug registration, and therefore, many diseases, especially the rare ones, remain untreated. One explanation for that could be the lack of knowledge in gene therapeutics, in particular, features of AAV vectors. To tackle this issue, further research is needed to achieve better optimization and higher effectiveness of AAV-based gene therapy approaches. This review discusses various AAV serotypes, some features of infection, tissue and organ tropism, efficacy in many human diseases, etc.

2. Brief History of AAVs’ Discovery

AAVs are small non-enveloped DNA viruses belonging to the Parvoviridae family, that were first isolated in 1965, as a contaminant in preparations of a simian adenovirus (Ad). The viruses were found incompetent to productively infect cells without a co-infection by a helper virus, usually an Ad or any type of herpesviruses, and thereby they were named as “adeno-associated”, and classified into the Dependovirus genus. After being regarded as defective viruses for a long time due to their codependency, later studies on AAVs disproved this theory and showed that they rather launch a latent infection in the host cell, that could convert to productive infection under stress. Although AAVs have a high seroprevalence in humans (it has been estimated that 50% to 96% of the human population is seropositive for the second serotype of AAV (AAV2) depending on age and ethnic group), they, however, were not linked to any disease neither in humans, nor in any other species. Different AAVs have not only been detected in primates isolates, but also from avian, caprine, bovine, and equine stocks.

3. Properties, Structure, and Genome Organization of AAVs

Aside from AAV5 being the most divergent, all AAVs share a similar structure and properties. AAVs are easy to manipulate, as their particles can maintain biological stability in extreme conditions of pH and temperature. They share a genome of approximately 4.7 kb single-stranded DNA packed into an icosahedral, non-enveloped capsid with a diameter of 20–25 nm. The AAV genome consists mainly of two viral genes: rep (replication) and cap (capsid), flanked by inverted terminal repeats (ITRs). As the ITRs have a palindromic nucleotide sequence, they create characteristic T-shaped hairpin structures, providing essential structural elements for viral genome replication and packaging. ITRs also play a regulatory role in viral gene expression and host genome integration. The open reading frame (ORF) of rep encodes several nonstructural proteins that are required for gene regulation, replication, transcription, and encapsidation, while the ORF of cap encodes three structural proteins: virion protein 1 (VP1), VP2, and VP3, with a molar ratio of 1:1:10 in AAV particles. Distinct tissue tropism of different AAV serotypes results from variations in the processing of this cap ORF, leading to variant immune and transduction profiles.

4. AAV Serotypes and Tropism

Depending on their serotype, AAVs can have specific tropism for specific organs and tissues of the body. There are different AAV serotypes that vary in many aspects. Next, each serotype will be separately discussed. Table 1 summarizes the characteristics and properties of AAV serotypes, and Figure 1 demonstrates their variant tropisms.

4.1. AAV1

The exact origin of the first serotype of AAV (AAV1) is still unknown, as it was not initially isolated from tissues, but as a contaminant of Ad stocks, and its antibodies were found both in humans and non-human primates (NHPs). This serotype uses sialic acid as its primary cellular surface receptor, and AAV receptor (AAVR) as a coreceptor. According to Rabinowitz J.E. et al., AAV1 does not bind heparin as it lacks R585 and R588, the amino acid residues required for such binding, and thereby it cannot be purified using heparin. Zolotukhin S. et al., developed a protocol for AAV1 chromatographic purification by iodixanol gradient centrifugation and anion-exchange chromatography. It can also be purified using mucin columns, as it can bind the sialic acid residues in mucin. Moreover, recombinant AAV1 (rAAV1) was not found to contain any detectable post-translational modifications (PTMs), according to a systematic analysis conducted on ten AAV serotypes by Mary B. et al., and it was the first viral vector to be approved for use in gene therapy. In 1999, Xiao W. et al., conducted a study to investigate viral vectors for gene therapy, as a result of which, AAV1 was found to be the most efficient serotype for skeletal muscles’ transduction. Many studies have since confirmed AAV1 high tropism to skeletal muscles of murine, canine, and NHP origins, compared to other serotypes. AAV1 was also found to achieve an efficient transduction of neurons and glial and ependymal cells in the murine brain. Moreover, it was found to be able to effectively transduce the heart, endothelial and vascular smooth muscles, and retina.

4.2. AAV2

AAV2 is considered the most studied serotype among all AAVs. It was first discovered in 1965 as a contaminant of simian Ad preparations. Later, in 1998, its primary cellular receptor, heparan sulfate proteoglycan (HSPG), was identified by Summerford C. and Samulski R.J., and the amino acid residues providing its affinity to HSPG were suggested, afterwards, as R585 and R588. Accordingly, rAAV2 can be purified using heparin column affinity chromatography. Nevertheless, the binding of AAV2 to its primary receptor was found to be insufficient for cell entry, so several coreceptors were later identified for it, including the human fibroblast growth factor receptor 1 (FGFR1), αVβ5 and α5β1 integrins, hepatocyte growth factor receptor (HGFR), laminin receptor (LR), and CD9. The capsid of rAAV2 is reported to acquire multiple PTMs, including ubiquitination, phosphorylation, SUMOylation, and multiple-site-glycosylation. As the most studied serotype, AAV2, in fact, has shown various tropisms for several tissues in NHP, murine, canine, avian, and human cell types, including renal tissue, hepatocytes, retina, non-mitotic cells of the central nervous system (CNS), and skeletal muscles. Nonetheless, broader tissue tropisms of AAV2 were enabled by the further innovation of mosaicism and cross-packaging (or cross-typing) of AAVs (explained in detail later in this article), where the viral genome of one serotype could be packaged into a capsid of another type, providing a wider transduction spectrum

4.3. AAV3

The third serotype of AAV (AAV3) was originally isolated from humans. Similar to AAV2, this serotype uses HSPG, FGFR1, and LR receptors, along with the human HGFR (hHGFR) receptor. Iodixanol gradient ultracentrifugation along with ion exchange chromatography have been used for AAV3 purification. PTMs of rAAV3 capsid include acetylation, phosphorylation, and glycosylation. Due to its inadequate transduction efficiency in vitro and in murine cell lines, AAV3 was mostly overlooked as a choice for gene therapy. However, as it has been later found to use hHGFR as a coreceptor, it showed extremely efficient transduction of human liver cancer cells as well as human and NHP hepatocytes. Since this selective tropism of AAV3 has been discovered, various studies have aimed at optimizing strategies to generate rAAV3 vectors with a higher transduction efficiency. The developed strategies suggested different approaches, mainly, capsid modification of AAV3 vectors and modification of hHGFR expression levels, along with the tyrosine kinase activity associated with it. AAV3 was also found to have specific tropism to cochlear inner hair cells, showing high in vivo transduction efficiency in a murine model.

4.4. AAV4

The fourth serotype of AAV (AAV4) is considered one of the most antigenically distinct serotypes. It has reportedly originated in NHPs, mainly in green African monkeys, as antibodies to its viral particles have been detected in their sera. A study of the AAV4 structure showed that its capsid surface topology shares a significant similarity with that of human parvovirus B19 and Aleutian mink disease virus. AAV4 uses a-2,3-O-linked sialic acid for cell binding and infection; accordingly, mucin columns can be used for AAV4 purification, based on its ability to bind sialic acid residues in mucin. In addition, as this serotype lacks heparin-binding activity, it cannot be purified using heparin column affinity chromatography like AAV2, however, ion-exchange chromatography procedures have been developed and proven a high purification efficiency. The only reported PTM of rAAV4 is ubiquitination of its capsid proteins. AAV4 is suggested to be able to transduce human/NHP cells, as well as cells of murine and canine origins. The specific tropism of AAV4 results in a transduction efficacy of specific cell types in the mammalian central nervous system (CNS), mainly the ependymal cells. Moreover, following subretinal delivery, AAV4 has showed stable transduction of retinal pigmented epithelium (RPE) cells of rodent, canine, and nonhuman primate models, a distinctive feature enabled by the specificity of its capsid. In a murine model, AAV4 has also shown a significant transduction rate of kidney, lung, and heart cells.

4.5. AAV5

As it was first isolated in 1983 from male genital lesions, AAV5 became the only AAV serotype to be isolated directly from a human tissue. This serotype is considered the most genetically divergent of all AAVs, with a variety of unique characteristics, such as the distinct size and function of its ITR regions, utilizing herpes simplex virus (HSV) as its helper virus for human infections, and using an atypical endocytic route as a pathway for viral entry. Another distinctive feature of AAV5 is its ability to transduce cells that cannot be transduced with AAV2, an exclusive advantage for gene therapy uses. AAV5 was also found to use sialic acid as its primary receptor, along with platelet-derived growth factor receptors (PDGFR) α and β as coreceptors. Similar to AAV1 and AAV4, mucin columns can be used for AAV5 purification, and ion-exchange chromatography procedures have also been developed for that aim. Capsid proteins of rAAV5 are reported to undergo multiple PTMs, including ubiquitination, phosphorylation, SUMOylation, and glycosylation. AAV5 proved to have a significant transduction efficiency for murine retinal cells, mainly for photoreceptor cells. In addition, AAV5 tropism has been investigated in the murine brain, and proved, as a result, a transduction competence for multiple neural cell types, including Purkinje cells, stellate, basket, and Golgi neurons, and it was able to reach to the inferior colliculus and ventricular epithelium. AAV5 is also known for its efficient transduction of murine airway epithelia by apical infection, vascular endothelial cells, and smooth muscles. It is also reported to have tropism for liver cells in mice.

4.6. AAV6

The classification of the sixth serotype of AAV (AAV6) is still a matter of controversy, as it presents high genomic similarity with both AAV1 and AAV2 serotypes, however, it has still been assigned its own serotype numbering. AAV6 has a serological profile almost identical to that of AAV1, and shares its sequence of coding region with a homology percentage of 99%, along with multiple regions identical to those of AAV2. Accordingly, it was suggested to be a naturally occurring hybrid resulting from homologous RECOMation between AAV1 and AAV2. AAV6 was first isolated from a human Ad preparation, and similar to AAV1, was found to bind sialylated proteoglycans, mainly α2,3-/α2,6-linked sialic acid, as its primary receptor, as well as binding heparan sulfate. As for its coreceptor, it binds epidermal growth factor receptor (EGFR). The only reported PTM of rAAV6 is acetylation of its capsid proteins. Similar to the previously described serotypes, AAV6 can be purified by either heparin or mucin column affinity chromatography, as it can bind both. AAV6 is reported to have tropism for a variety of tissues, including airway epithelia of murine and canine models, murine liver cells, and skeletal muscles of murine and canine models, with a transduction efficiency even higher than that of AAV2, cardiomyocytes in murine, porcine, canine, and in sheep models.

4.7. AAV7

The seventh serotype of AAV (AAV7) was first isolated in 2002 from NHP tissues, specifically, from Rhesus macaque monkeys. Its mechanisms of cell binding and cell entry are still unknown, but it is established that this serotype does not bind heparin, or any other glycan in general. Capsid proteins of rAAV7 undergo multiple PTMs, including glycosylation, primarily, along with phosphorylation, SUMOylation, and acetylation. A study by Calcedo R et al., investigated the epidemiology of AAV-neutralizing antibodies in the worldwide population, and found that the seroprevalence of AAV7 antibodies is relatively low in humans, an advantage of this serotype to be used in clinical applications. Viral vectors based on AAV7 proved a high efficiency of transduction for skeletal muscle cells in murine models, similar to that achieved by AAV1, and higher than AAV2. This serotype also proved a strong tropism to hepatocytes in murine and human tissues. In CNS of NHPs, AAV7 viral vectors were found to achieve a robust transduction mainly in cortical and spinal tissues. Moreover, AAV7-based viral vectors can, reportedly, achieve a significantly high transduction rate of murine neurons and photoreceptor cells in the retina both in vivo and ex vivo. AAV7 vectors also appear to have a limited tropism to vascular endothelial cells, that could be relatively enhanced through proteasome inhibition, and an in vivo transduction preference for epicardium cells in murine cardiac tissue.

4.8. AAV8

Similar to AAV7, the eighth serotype of AAV (AAV8) was first isolated in 2002 from Rhesus macaque monkeys. As a primary receptor, AAV8 binds LR, the same receptor used by AAV2 and AAV3. Various procedures for rapid and scalable purification of AAV8 have been developed since its discovery, including, for example, dual-ion-exchange chromatography, or iodixanol gradient centrifugation. Phosphorylation, glycosylation, and acetylation are the three PTMs reported for rAAV8 capsid proteins. AAV8 is best known for its strong tropism to liver cells, and accordingly, its transduction efficiency of hepatocytes, which is far stronger and faster than those of all other AAV serotypes in different models, including murine, canine, and NHP. Following systemic delivery in murine models, AAV8 was proven to be the most efficient serotype for transduction of both skeletal and cardiac muscles, owing to its ability to cross the blood vessel barrier, a feature that both AAV1 and AAV6 lack, limiting their efficiency of muscle transduction to local delivery only. AAV8 could also achieve a successful in vivo transduction of murine pancreatic cells, following localized delivery. Moreover, a high-rate transduction of murine renal cells could be reached by local direct delivery of AAV8 viral vectors into the kidney tissue. AAV8 was also found to achieve an efficient transduction of different cells in the murine retina, including amacrine, Müller, and putative bipolar cells, along with some horizontal cells and cells in the ganglion cell layer (GCL). AAV8 transduction efficiency appears to be susceptible to proteasome levels in some tissues, and accordingly, could be increased using proteasome inhibitors.

4.9. AAV9

The ninth serotype of AAV (AAV9) was first identified in a human isolate in 2004, and was named a new serotype as it had a serological profile distinct from the previously known AAVs, however, it was suggested to be closely related to clades containing AAV7 and AAV8. As a primary receptor, AAV9 uses terminal N-linked galactose, and it is also suggested to bind a putative integrin, along with LR as coreceptors. Scalable simple purification protocols have been developed for AAV9 purification, including ion-exchange chromatography and sucrose gradient centrifugation. Capsid of rAAV9 has one of the highest totals of PTMs, including multiple ubiquitination, phosphorylation, SUMOylation, and glycosylation modifications, along with acetylation. In most tissues, AAV9 seems to achieve cell transduction with efficiency superior to other AAVs. For example, in a study aimed to investigate AAV1–9 distribution following systemic delivery in a murine model, AAV9 has shown rapid-onset, the best genome distribution, and the highest protein levels, in comparison with all other AAVs. Moreover, in the CNS of murine, NHP, and feline models, it has a unique feature compared to other serotypes, as it can cross the BBB and transduce not only neuronal but also non-neuronal cells, including astrocytes, that cannot usually be transduced by other AAVs, also showing tropism to photoreceptor cells in the retina. Viral vectors based on AAV9 have also proven to be more efficient than those of AAV1 and AAV8 (in some cases 5–10-fold higher than AAV8), for murine, NHP, and porcine cardiac muscle transduction, enabled with another distinctive feature of AAV9—its ability to traverse the physical barrier of vascular system endothelia. Another example of AAV9 superiority over other AAVs was presented in a study by Inagaki K et al., where the serotype achieved robust transduction of murine hepatocytes, skeletal muscles, and pancreatic cells. AAV9-based viral vectors also appear to be tropic to murine photoreceptor cells, renal tubular epithelium cells, Leydig cells in the testicular interstitial tissue, and alveolar and nasal epithelia.

4.10. AAV10 and AAV11

The ninth and tenth serotypes of AAV (AAV10 and AAV11) were first found and described in 2004 in NHP isolates, namely from cynomolgus monkeys, with capsid proteins of great resemblance to AAV8 and AAV4, respectively, resulting in serological cross-reactivity with those two serotypes. However, antisera against AAV10 and AAV11 were not found to have any cross-reactivity against those of AAV2, which recommended them as good viral vector candidates for gene therapy in individuals having antibodies against the latter. It remains unknown what cellular receptors and coreceptors AAV10 and AAV11 use for cell binding and entry; therefore, procedures describing their purification protocols are generally based on iodixanol gradient centrifugation. Similar to AAV9, capsid of rAAV10 has one of the highest totals of PTMs, including mainly multiple glycosylation and phosphorylation modifications, along with ubiquitination, SUMOylation, and acetylation. A study investigating biological distribution of both AAV10 and AAV11 in monkeys suggested them to be tropic to NHP intestinal cells, hepatocytes, lymph nodes, and less frequently, to renal cells and adrenal glands. AAV10 was also suggested to have tropism to murine small intestine and colon cells. Compared to AAV8 and AAV9, AAV10 appears to have the largest tropism range to murine retinal cells, as it can reportedly transduce a variety of cell types, including RPE, cells in the ganglion cell layer, several cell types in the inner nuclear layer, photoreceptors, and a highly efficient transduction of horizontal cells. Following intravenous delivery, AAV10 was found to target murine liver and lung cells, however, upon localized delivery, it transduced murine renal and pancreatic cells. As for AAV11, it was found to have mild tropism to NHP CNS, mainly to the cerebrum and spinal cord. A recent study of neural gene therapy using rAAV11 found that murine projection neurons and astrocytes could also be targeted using this serotype.

4.11. AAV12

The twelfth serotype of AAV (AAV12) was first isolated from a simian Ad stock, and then characterized as a novel serotype, as it exhibited distinctive biological and serological properties. Although it was proven that AAV12 does not use heparan sulfate proteoglycans or sialic acids for attachment and cell entry, it remains unknown how exactly it binds target cells. However, according to a study investigating components of a potential receptor complex for AAV12, mannose and mannosamine were suggested as components of such complex, as they inhibited AAV12 cell transduction. Moreover, being resistant to neutralization by human antibodies, AAV12 represents a good candidate for human gene therapy applications. AVB Sepharose affinity chromatography has been used for purification of AAV12. In murine models, it has shown tropism to salivary glands and muscles. It has also shown strong, localized in vivo tropism to murine nasal epithelia following intranasal administration.

4.12. AAV13

The thirteenth serotype of AAV (AAV13) is another simian Ad that appears to bind HSPG, although its primary cell receptor remains unknown. It was also found to share structural similarity with AAV2 and AAV3, making it the closest related AAV to those two serotypes, with a capsid conserving all AAV capsids’ structural features, but there are only limited data on this serotype tropism and transduction efficiency.

4.13. Novel Hybrid AAV Vectors

In addition to the natural AAV serotypes described above, novel AAV vectors have been developed during the last two decades, and are still being developed. Using different engineering strategies, novel hybrid vectors have been generated in order to enhance their transduction, modulate their immunogenicity, or limit their tropism to specific cells. There has been different types of such engineered novel vectors, including mosaic, chimeric, and combinatorial vector libraries. Mosaic vectors have multiple subunits of various serotypes in their capsid, chosen according to their properties of receptor binding and intracellular trafficking. In chimeric virions, the capsid usually has modified protein generated by domain swapping and DNA shuffling strategies to alter specific amino acids. Combinatorial vector libraries also use DNA shuffling and error-prone PCR methods to generate AAV libraries of novel serotypes with mixed genomes.

5. AAV as Viral Vectors for Gene Therapy Applications

A variety of AAV features have made it an appealing viral vector candidate to be used in gene therapy applications. To begin with, AAVs are non-pathogenic viruses, since no diseases have been linked to them. AAV vectors have also proven their ability to provide stable integration into the target genome, and such feature is highly needed for gene therapeutic uses considering the high level of expression that could be maintained as a result, without affecting the target cell functions in the long term. Moreover, having only ITRs, AAV vectors cannot interfere with the inserted gene regulation either. More specifically, a unique feature of AAV vectors, contrary to all currently available gene-editing platforms, is utilizing the homologous recombination pathway, which does not involve exogenous nucleases, providing, therefore, a highly accurate editing process that preserves genome integrity without adding to the mutational burden of the target site. Thanks to such unique gene-editing properties, AAV vectors are currently the leading platform for in vivo gene therapy delivery. Another attractive feature is the very broad range of cells, tissues, and hosts that AAV can efficiently transduce in vivo and in vitro, including dividing and non-dividing cells in humans, and NHP, murine, canine, feline, and a variety of other models. In addition to the genetic properties, AAVs’ distinct physical properties represent more reasons why they should be used for gene therapy, such as easy manipulation, resistance to pH changes, heat changes, and detergents. Next, we present various studies that investigated AAV vectors for a wide range of gene therapy applications (reviewed in Table 2).

5.1. AAV Viral Vectors for Gene Therapy of the CNS

AAV-mediated CNS gene therapy was first believed to predominantly target neurons, with lesser chance to affect other cells and tissues in the CNS, a fact that was later proven to be inaccurate in many studies. For a variety of neurodevelopmental and neurodegenerative diseases, AAV-mediated gene therapy has been tested using different administration routes, including intraparenchymal, intrathecal, intracerebroventricular, and intracisternal injection, many of which have shown promising results.

Parkinson’s disease (PD) has been one of the most studied neurological disorders as a target for AAV-mediated gene therapy. In a phase I clinical trial, Kaplitt et al., investigated an AAV-mediated gene therapy approach for advanced PD patients, where serotype 2 was used as a vector for unilateral subthalamic delivery of the glutamic acid decarboxylase (GAD) gene. Providing a significant improvement in motor function scores up to 12 months after surgery, the approach was found to be safe and well-tolerated in patients. A similar double-blind, controlled, randomized clinical trial conducted later by LeWitt et al., investigated the same AAV2-GAD vector for bilateral subthalamic delivery in advanced PD patients, and showed similar results of safety and improvement of motor function. Bartus et al., also tested the bilateral stereotactic delivery of AAV2-neurturin in PD patients of an open-label clinical trial, the initial obtained data of which supported the feasibility, safety, and good tolerance of the approach as a potential treatment for PD. However, bilateral intra-striatal infusion of an AAV2 vector containing the aromatic L-amino acid decarboxylase (AADC) gene in moderately advanced PD patients led to an improvement in PD rating scales that was associated with a risk of intracranial hemorrhage in patients, along with headaches. As for sustainable transgene expression, a clinical trial conducted by Mittermeyer G. et al., investigated the potentials of rAAV2 carrying the aromatic L-amino acid decarboxylase gene (rAAV2-AADC). In the trial, 10 patients with moderately advanced PD received bilateral infusions of recombinant vector into the putamin, showing good tolerance and a stable expression of transgene that lasted for the following 4 years, although higher vector doses were suggested for further studies. In children with AADC deficiency, the same delivery route for the same vector (rAAV2-AADC) was also assessed in an open-label phase I/II clinical trial. The therapy was well-tolerated in general, providing evidence for potential improvement of motor function.

Similarly, spinal muscular atrophy (SMA) has always represented an attractive candidate for gene therapy, being caused by a single gene defect that affects the survival motor neuron (SMN) protein. Therefore, SMA has been suggested as a target for AAV-mediated therapeutic approaches, mainly using AAV9. An open-label, phase I clinical trial was designed by AveXis, Inc. in 2014 to assess the safety and efficacy of AA9-SMN as a treatment for SMA. Following single-dose intravenous administration of the vector, a significant improvement of the motor function in all 15 patients was observed, reflected by their ability to perform different activities, such as unassisted sitting and walking, oral feeding, and speaking, with no reported motor function regression at the two-year follow-up. A long-term safety assessment, however, was recommended.

Lysosomal storage diseases (LSDs), another group of neurodegenerative diseases, have also been extensively targeted by AAV-mediated gene therapy. One example of which is mucopolysaccharidosis type VII (MPS VII or Sly disease), a disease that results from genetic deficiency of beta-glucuronidase (GUSβ). In the murine model, AAV-mediated gene therapy has been shown to provide stable expression of the deficient enzyme upon single administration, that was adequate for phenotype correction in the liver and most of the neuraxis. As for neonatal murine model, intravenous delivery of rAAV-GUSβ proved to yield therapeutic levels of the deficient enzyme in multiple organs, including ones of the CNS, with the gene expression not being affected by rapid growth and differentiation of tissues. The canine model of MPS VII has also shown promising therapy results following rAAV-GUSβ intrathecal injection of serotypes 9 and the NHP-derivate AAVrh10, as high expression levels of GUSβ were detected in the CNS tissues, with the enzyme in brain tissue homogenates showing over 100% normal activity. Another type of MPS, MPS IIIA, has also been assessed for gene therapy in the canine model using AAV9 carrying the deficient enzyme’s gene. Following intra-cerebrospinal fluid (CSF) delivery, the administered vector provided sustained and widely distributed transgene expression with no toxicity for a duration of seven years after therapy. Metachromatic leukodystrophy (MLD) is also one of the LSDs that results from arylsulfatase A (ARSA) enzyme deficiency and has been targeted by AAV-mediated therapeutic approaches. In the murine model of MLD, as well as in NHPs, serotypes 1, 5, 9, and rh10 carrying the ARSA gene have provided supporting results of their therapeutic potentials as gene therapy viral vectors. GM2 gangliosidoses is another example of lysosomal storage diseases that have been assessed for AAV-mediated gene therapy, including Tay-Sachs disease (TSD) and Sandhoff disease (SD). Preclinical data from many in vivo studies have provided evidence of AAVs’ efficacy for GM2 gangliosidoses in murine, ovine, and feline models. Clinically, there has been trials applying AAV-mediated gene therapy for different LSDs throughout the last decades with variant outcomes. In 2018, four children with asymptomatic or early-stage MLD underwent a phase I/II trial for gene therapy using AAVrh.10-hARSA. Although there was a significant elevation in ARSA levels recorded in the CSF following intracerebral vector delivery, no clinical improvement was noticed compared to the control group. As for gangliosidosis, the first clinical trial for gene therapy of Tay-Sachs disease using an AAV vector was conducted by Taghian et al., in 2020. The treatment proved to be safe for the two treated children and resulted in a broad distribution of the transgene in CNS.

Canavan disease (CD) is another rare inherited leukodystrophy belonging to LSDs, that has been targeted by AAV-mediated gene therapy. CD results from aspartoacylase (ASPA) enzyme deficiency, that leads to N-acetylaspartic acid (NAA) accumulation in the brain, causing white matter degeneration. In a murine model, rAAV2-ASPA delivery into the striatum and thalamus of the brain resulted in an increased ASPA activity and, thereby, decreased NAA accumulation and white matter degeneration. However, areas remote from the injection site, such as the cerebellum, were not affected. In 2002, Janson et al., suggested a clinical protocol using rAAV2-ASPA for gene therapy in CD patients, and currently there are several ongoing clinical trials testing different serotypes of rAAV (including 2, 9, and olig001), carrying the ASPA gene for CD gene therapy.

Krabbe disease, also known as globoid cell leukodystrophy (GLD), causes demyelination in a similar way. The diseases results from deficiency of the lysosomal enzyme galactocerebrosidase (GALC), leading to accumulation of its substrate, psychosine, which affects both the central and peripheral nervous systems. During the last two decades, a large number of in vivo studies have been conducted to investigate different AAV serotypes as viral vectors for gene therapy of GLD in different animal models, including murine and canine. Intracerebral delivery of rAAV1-GALC has been tested in the murine model of GLD in an in vivo study conducted by Rafi et al.. The approach resulted in sustained expression of the deficient enzyme, and thereby positively affected myelination status, and animals’ lifespan. However, both treated and untreated mice died with similar symptoms, suggesting that the used approach should be initiated prior to symptoms’ onset. rAAV2/5-GALC has also shown therapeutic efficacy in the murine model of GLD following intracranial delivery. In the study conducted by Lin et al., in 2011, mice treated with rAAV2/5-GALC showed wide dispersion of the GALC transgene across the CNS, reaching areas remote from the injection site. Moreover, rAAV2/5-GALC delivery resulted in a reduced loss of oligodendrocytes and Purkinje cells, along with a significant improvement of neuromotor function and a prolonged lifespan of treated mice. Karumuthil-Melethil et al., conducted another preclinical study using recombinant vectors AAV9, AAVrh10, and AAV-Olig001, carrying the GALC gene, for GLD gene therapy in the murine model, following lumbar intrathecal delivery. All three serotypes provided wide distribution of the transgene across the CNS and liver, resulting in a significant improvement of myelination, and a prolonged lifespan, with AAV9 being the most effective when combined with bone marrow transplantation. AAV9 and AAVrh10 have also been tested for GLD therapy in the canine model. Combined intravenous and intracerebroventricular delivery of AAVrh10 encoding canine GALC (AAVrh10-cGALC) resulted in delayed symptoms onset, prolonged lifespan, correction of biochemical defects, and also positively affected neuropathology in treated animals. Similarly, AAV9-cGALC has shown promising therapeutic potency in the GLD canine model. Reportedly, intrathecal delivery of AAV9-cGALC resulted in increased activity of the deficient enzyme and, therefore, normal levels of its substrate. It also improved myelination, and decreased inflammation both in the CNS and PNS, which, along with prevention of clinical neurological dysfunction, resulted in a significantly prolonged lifespan of treated dogs, compared to the control group. However, sufficient dosing was found to be critical, as high doses significantly extended the lifespan even for post-symptomatic subjects, and a 5-fold lower dose of the vector resulted in an attenuated form of disease.

For ocular diseases, AAV viral vectors have also provided great therapeutic opportunities both in vivo and in human clinical trials. In a study by Petrs-Silva et al., the efficacy of intraocular transduction of rAAV serotypes 2, 8, and 9 was investigated in mice for targeting ocular neurovascular and retinal diseases. Besides transduction of retinal cells, both serotypes 8 and 9 efficiently transduced the ganglion cell layer, providing evidence for their potentials in therapeutic approaches of ocular diseases. Moreover, AAV2/7 and AAV2/8 hybrid serotypes have achieved high transduction rates of the murine photoreceptors, showing promising potentials for treatment of inherited photoreceptor diseases. AAV2/6 has also shown an efficient transduction of murine cone photoreceptors following subretinal injection. In humans, AAV2/4 has been used in a clinical trial for treatment of childhood blindness caused by Leber Congenital Amaurosis (LCA) disease, mainly by a mutation in the retinal pigment epithelium-specific protein (RPE65). Over a follow-up period between 1 and 3 years, subretinal injection of AAV2/4-RPE65 showed good tolerance both systemically and locally, with no adverse effects, and resulted in an improvement of visual function presented by different parameters in different patients, including improvement of visual acuity and color vision, as well as a reduction of visual fatigue or photophobia. Another example of AAVs’ applications in ocular disease therapy is a phase I/II clinical trial by MacLaren R et al., that has aimed to treat blindness caused by choroideremia, an X-linked recessive disease that results from a mutation affecting retinal escort protein 1 (REP1). In the trial, AAV2-REP1 resulted in improvement of retinal sensitivity in all six patients, following subretinal injection, with two of them having significant increases in visual acuity, supporting further consideration of the tested therapeutic approach. Various other clinical trials have applied AAV-mediated gene therapy for ocular diseases, and many of which have presented promising results, using mainly AAV2 and AAV8 (detailed in Table 2).

Similar to ocular diseases, hearing disorders have also been suggested for AAV-mediated gene therapy. In a porcine model, Lalwani A. et al., tested AAV9 intracochlear delivery to assess its efficacy as a vector for gene therapy of hearing disorders, and demonstrated, as a result, transgene expression in the inner ear of animals following administration.

5.2. AAV Viral Vectors for Gene Therapy of Respiratory Diseases

For over 20 years, AAV vectors have been vastly investigated for gene therapeutics of respiratory diseases, both in preclinical experiments and human clinical trials. However, a key limitation was that many AAV serotypes cannot efficiently transduce airway epithelial cells through the apical surface, suggesting molecular modifications of such serotypes to enhance their transduction efficiency. Cystic fibrosis (CF) represents one of the most studied diseases as a target for AAV-mediated gene therapy. In rabbits, AAV has proven to promote an efficient and stable gene transfer of the cystic fibrosis transmembrane conductance regulator (CFTR) gene into the airway epithelium, indicating, as a result, the vector potential to be used for gene therapy. Subsequently, since 1998, clinical trials have started using recombinant AAV viral vectors to target different sites of the airway epithelium of CF patients, using variant administration routes. The very first clinical trial to do so used the maxillary sinuses for delivery of recombinant AAV2 containing the CFTR gene (AAV2-CFTR) in ten CF patients, demonstrating a safe, successful transduction of targeted cells and a detected function restoration of the sinuses. Soon after, a following phase II double-blind clinical trial tested unilateral administration of the same vector into the sinus for 23 CF patients, with an in-patient control, achieved by administering a placebo drug into the other sinus. The approach again showed safety and good tolerance, although it did not confirm clinical effectiveness of the treatment. Aitken et al., also tested AAV2-CFTR in a phase I clinical trial for twelve mild CF patients using aerolization by nebulation for delivery, confirming the approaches safety, but failing to yield an effective clinical treatment. Further trials on AAV2-CFTR with single or repeated dosing have yielded similar results of safety and good tolerance, providing little evidence of clinical treatment after intranasal and endobronchial delivery. In order to optimize such therapeutic approaches and produce a functional CFTR in CF patients, further modifications of recombinant AAV vectors have since been developed. Alpha-1 antitrypsin (α1AT or AAT) deficiency is another lung and liver disease that has been extensively studied as a target for AAV-mediated gene therapy both in vivo and in humans. Reportedly, intravenous delivery of recombinant AAV vector carrying the human alpha-1 antitrypsin gene (AAV-hAAT) in the murine model resulted in potentially therapeutic serum levels of AAT. Further research found that intrapleural delivery of rAAV2-hAAT or rAAV5-hAAT could achieve higher AAT levels both in lungs and serum compared to intramuscular delivery in C57BL/6 mice, with the rAAV5 showing 10-fold higher effectiveness than rAAV2. However, rAAV6/2-hAAT has been shown to transduce murine lung cells even more efficiently than rAAV5 both in vivo (in murine lung cells) and in vitro (in human airway epithelial cell culture). Similarly, rAAV8-hAAT has also been shown to provide murine lung cells’ transduction superior to that of rAAV5 following intratracheal delivery, as it resulted in 6-fold and 2.5-fold AAT levels in serum and broncho-alveolar fluid, respectively, and a high transduction rate of murine hepatocytes. Chiuchiolo M et al., also proved the safety of rhAAV10-hAAT as a viral vector for treatment of AAT in wild-type murine and NHP models. Besides, the delivered vector resulted in persistent expression of the transgene in chest cavity cells of both models, suggesting the efficacy of the tested therapeutic approach. Examples of other rAAV vectors’ therapeutic potentials for AAT treatment have been shown in a variety of other preclinical studies, including rAAV1-AAT, rAAV2/9-AAT, and rAAV6.

AAVs have also been tested to develop therapeutic approaches for other lung diseases, such as asthma and surfactant B deficiency. A preclinical study by Zavorotinskaya et al., investigated the efficacy of rAAV carrying the interleukin 4 gene (IL-4) as a vector for gene therapy of allergic asthma, upon intratracheal delivery into the murine model. Showing a significant inhibition of airway eosinophilia and mucus production along with a reduction in airway hyper-responsiveness and asthma-associated cytokines levels, obtained data suggested rAAV efficacy for gene therapy of the studied disease. Kang et al., have recently tested an engineered rAAV6/2 vector carrying human or murine surfactant protein B gene (SFTPB) in a murine model. Mutations of this gene cause surfactant protein B deficiency (SPB) in humans, a rare genetic condition with a very poor prognosis. In their study, Kang et al., demonstrated efficient transduction of the airway and alveolar epithelium by engineered rAAV6/2-SFTPB following intratracheal administration into a murine model of SPB. As a result, the administered vector was well-tolerated with no adverse effects. Moreover, rapid, long-term restoration of the deficient SPB protein was reported, along with an improvement of lung function, leading, subsequently, to an extended survival.

5.3. AAV Viral Vectors for Gene Therapy of Muscle Diseases

Having a large, body-distributed mass, and myofibers with a long half-life time makes muscles an attractive target for gene therapy, also considering the minimal invasiveness of the intramuscular delivery route. Muscular dystrophies (MD) constitute a large group of muscle diseases that have been studied for a long time and proved to be a good target for AAV-mediated gene therapy. For example, AAV1 carrying the follistatin gene, an antagonist of muscle growth negative regulator, has been shown to promote sustained improvement in muscle size and strength in NHPs following intramuscular administration. There has also been many reports of both histopathological and functional sustained muscle restoration as a result of using AAV-mediated therapeutic approaches in animal models of Duchenne muscular dystrophy (DMD), and Limb-Girdle muscular dystrophies (LGMD). As for clinical research, there have been several registered clinical trials of AAV-mediated gene therapy for muscular dystrophies. The first clinical study was a randomized, double-blind, placebo-controlled phase I clinical trial, conducted in 2012 by Bowles D et al., which used AAV2.5 carrying the mini-dystrophin gene for intramuscular administration in DMD patients. As a result, the administered vector was found to be safe and well-tolerated, and transgene DNA was detected in all patients. Similarly, other clinical trials were started in 2017 and 2018 to test AAV-micro-dystrophin efficacy for treatment of DMD (details in Table 2).

5.4. AAV Viral Vectors for Gene Therapy of Cardiovascular and Blood Diseases

Cardiovascular diseases make another attractive target for gene therapy, being a leading cause of death globally with their high incidence and mortality rates. As mentioned before, AAV serotypes 6, 8, and 9 have been shown to efficiently transduce cardiac cells in different animal models, and accordingly, they have been used for therapeutic purposes in different cardiovascular diseases.

In the search for an effective gene therapy platform for heat failure (HF), White J et al., published a study in 2011, in which they suggested a novel technique for AAV-mediated myocardial gene therapy using molecular cardiac surgery. Using AAV6 in an ovine model, the suggested approach resulted in a global transgene expression, that was cardiac-tropic and substantially more robust and targeted, compared to that of intramuscular or intracoronary injection. Furthermore, a randomized phase I/II AAV1-based clinical trial for heart failure treatment was conducted in 2013, where the researchers used a sarcoplasmic reticulum calcium ATPase gene (SERCA2a), the product of which was suggested to play a key role in HF pathology. As a result, adverse effects, including death, were found to be highest in the placebo group, and lowest in the high-dose group, with evidence of long-term transgene expression. However, in the low-dose and mid-dose groups, adverse effects were also found to be high but delayed.

Hemophilia, an inherited disease that is caused either by deficiency of blood clotting factor VIII (type A) or IX (type B), is another example of diseases that have been targeted by AAV-mediated gene therapy. rAAV6 and 8 expressing the canine gene of FVIII have been shown to restore physiologic levels of the deficient factor in a canine model for three years following intravenous administration, without any toxicity or immune reactions. The same vectors could result in a similar effect in the murine model; however, neutralizing antibodies against cFVIII were detected in the mice sera. As for hemophilia B, intravenous administration of rAAV8 and 9 carrying the IX factor gene in a murine model resulted in a significant increase in transgene expression and therefore in IX factor levels, with a decreased proinflammatory risk.

5.5. AAV Viral Vectors for Gene Therapy of Liver Diseases

AAV-based gene therapy plays a significant role in liver diseases, as it is, in some cases, an alternative to the only effective therapy, which is liver transplantation. In addition to the previously mentioned diseases affecting the liver, that have been targeted by AAV-base gene therapy, such as CF, AAT deficiency, and hemophilia, there are other liver diseases that have been targeted and continue to be, using AAV8, mainly.

Wilson’s disease (WD) is a rare autosomal recessive disease caused by mutations in the copper transporter gene, ATP7B, resulting in copper accumulation mainly in the liver, along with some other organs. A recent in vivo study, conducted by Murillo et al., proved the efficacy of an AAV-based gene therapy for WD in a murine model of the disease. The vector used in the study was AAV8 carrying an optimized short version of the ATP7B gene (AAV8-mini ATP7B) adjusted to the right size, so it could be produced and delivered more efficiently. As a result, intravenous administration of the recombinant vector to 6- and 12-week-old WD mice could restore copper homeostasis, with 20% hepatocyte transduction being sufficient for correction.

Crigler-Najjar syndrome (CNs) type 1 is another autosomal recessive liver disease caused by deficiency of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), which leads to severe inherited unconjugated hyperbilirubinemia. There is currently an ongoing clinical trial investigating AAV8-UGT1A1 as a vector for gene therapy in children with CNs; however, as the preclinical data of the trial suggest a negative effect of liver cells’ proliferation on the efficacy of gene therapy in children, Shi et al., suggested to optimize the approach by starting therapy at a specific age and combining it with an immune suppression regimen. In their in vivo study, Shi et al., found that a stable correction was achieved when AAV8-UGT1A1 was administered to CNs rats at the 28th postnatal day, coupled with a rapamycin-based immunosuppression regimen delivered intraperitoneally.

5.6. AAV Viral Vectors for Gene Therapy of Endocrine Disorders

Being a major health issue for humans all around the world, with relatively high prevalence estimates, endocrine disorders have always been in the focus of research for therapeutic approaches and techniques. Accordingly, rapid developments of diagnostic techniques, along with the better understanding of endocrine disorders’ pathophysiology and molecular bases, helped in developing different therapies, such as hormonal replacement therapies, for example. However, as these approaches have mostly focused on improving the patient’s quality of life, reducing or reversing symptoms, rather than targeting the underlying defect, the resulting effect has not always been sufficient, which highlighted the need for gene therapy approaches, including AAV-based ones.

Type 1 diabetes mellitus (T1DM) is one of the endocrine autoimmune disorders that has been extensively studied as a target of gene therapy. T1DM is characterized by self-destruction of insulin-secreting islet β cells, resulting from a wide variety of causative factors. In non-obese diabetic (NOD) mice, administration of recombinant adeno-associated virus serotype 8 carrying DNA of mouse insulin promoter (dsAAV8-mIP) has been shown to prevent hyperglycemia in a dose-dependent manner. High levels of mouse interleukin 10 (mIL-10) achieved following rAAV2-IL-10 intramuscular administration also proved to have a positive effect in NOD mice by decreasing autoimmunity, and thereby hyperglycemia. Similarly, negative regulation of the immune response by programmed death ligand 1 (PDL1) was achieved in NOD mice following intraperitoneal delivery of AAV8-PDL1, which protected β cells. Currently, there is an ongoing clinical trial investigating AAV8 containing a transgene for the fragment antigen-binding region of anti-vascular endothelial growth factor (anti-VEGF fab), as a vector for gene therapy of diabetic retinopathy, delivered in the suprachoroidal space.

Autoimmune polyglandular syndrome type-1 (APS1) is another disorder characterized by multiple endocrine abnormalities, resulting from a monogenic defect in the autoimmune regulator (AIRE) gene. Recently, Almaghrabi tested AAV9-AIRE as a potential gene therapy for APS1. As a result, AAV9-AIRE, following intra-thymic administration in a murine model, showed high transduction efficiency, along with restoration of AIRE expression in the thymus. Subsequently, a significant reduction of serum auto-antibodies was detected in treated mice, with a relatively normal tissue morphology showing no lymphocytic infiltrations.

5.7. AAV Viral Vectors for Gene Therapy of Cancer

Despite the variety of therapeutic approaches developed so far for cancer, including chemotherapy, radiotherapy, surgery, and different medications, cancer is still a huge health issue and a leading cause of death worldwide. Several AAV-mediated cancer gene therapy approaches have been reported so far, including suicide gene, RNA-interference, and anti-angiogenesis gene therapies.

In AAV-mediated suicide gene therapy, an AAV-based system with herpes simplex virus type-1 thymidine kinase and ganciclovir (AAVtk/GCV) has been used. This system was found to exhibit a significant in vitro and in vivo tumor-suppressor efficacy in human head and neck cancer xenografts in a murine model, and murine models of bile duct cancer and bladder carcinoma.

As for AAV-mediated RNA-interference cancer gene therapy, an AAV vector is used to provide a stable expression of short hairpin-structured RNA (shRNA) for gene knockdown applications. This approach could induce a strong androgen receptor (AR) gene silencing in a murine model of prostate cancer following intravenous administration. It has also been tested in a murine model of hepatocellular carcinoma and was found to induce tumor-specific apoptosis, resulting in a significant inhibition of cancer cell proliferation without toxicity.

AAV-mediated anti-angiogenesis cancer gene therapy targets factors that can regulate a cancer cell angiogenesis process. VEGF, being an important factor for angiogenesis, has been targeted in a murine model of breast carcinoma using AAV2 carrying transgene of VEGF Trap protein (a pseudo high-affinity receptor). The approach resulted in significant suppression of tumor growth and prevention of spontaneous pulmonary metastases. Another factor that has been targeted by this approach is pigment epithelium-derived factor (PEDF), a highly potent angiogenesis inhibitor. In a murine colorectal peritoneal carcinomatosis model, AAV2 carrying the human gene of PEDF was found to induce significant tumor suppression, inhibit metastases, and prolong survival time. Similarly, kallistatin is another anti-angiogenesis factor that has been targeted using an AAV-mediated murine model of hepatocellular carcinoma, and it provided a similar efficacy as AAV-kallistatin-induced potent cancer cell apoptosis.

6. Challenges and Limitations of AAVs for Gene Therapy AAV-Mediated Applications

Despite the many advantages AAVs provide as viral vectors for gene therapy of various diseases, and the many improvements and molecular modifications they have undergone since their first discovery, AAVs still have some limitations that can result in impeding impacts on their applications in some cases. One example of such major limitations is the limited cloning capacity of AAVs, that is ~4.5 Kb. Moreover, AAVs need to converse into double-stranded DNA, and may cause a delay in transgene expression following delivery, compared to double-stranded vectors. Although it can be dose-dependent in some cases, preexisting immunity against some serotypes can also be a limiting factor.

Preexisting immunity, or an immunity response occurring after the first introduction of a viral vector, can be a major obstacle in the development of gene therapy approaches based on AAV or other viral vectors, and their application in clinical practice. Neutralizing antibodies are often found in the human population with a high prevalence that varies depending on the virus serotype and the geographic location of the population. Moreover, in a number of diseases, multiple administration of an AAV-based drug may be required, which can result in developing an immune response against the viral vector. Neutralizing antibodies can have a significant impact on the efficiency of gene transfer in gene therapy. Consequently, many patients with genetic diseases will not be able to benefit from such gene therapy medications.

Furthermore, although AAVs have not been linked to human pathologies or diseases, wild-type AAVs are widely distributed in the human population, and despite having a low immunogenicity profile, an immune response was observed in humans as a result of gene therapy using AAVs. To date, the impact of such anti-AAV immune response on gene therapy is still not entirely understood, however, its mechanisms are being actively explored. For example, systemic delivery of AAV vectors, while having neutralizing antibodies, has been shown to result in accumulation of vector genomes in lymphoid organs. Whereas the efficiency of liver transduction while having binding antibodies (indicative of a previous infection, but not neutralizing the virus), on the contrary, increases. The role of neutralizing antibodies in activating the complement system has also been studied. Individuals seropositive for AAV have high titers of IgG1, IgG2, and IgG3. It is known that IgG1, IgG2, and IgM highly correlate with the level of neutralizing antibodies, and IgG1 levels increase after gene therapy with AAV. Additionally, IgG3 correlates with the level of T-cell reactivity against AAV vectors. From a clinical point of view, neutralizing antibody titers are of a great significance, as having neutralizing antibodies against a specific AAV serotype highly affects gene therapy effectiveness upon using this serotype. Although methods for detecting neutralizing antibodies are poorly standardized, existing research data indicate that the prevalence of neutralizing antibodies against AAV2 is about 40%. It has been shown that neutralizing antibodies can trigger elimination of the vector by the immune system. At the same time, viral vectors can accumulate in the spleen, not reaching the liver. Therefore, researching mechanisms to establish and develop effective methods for preexisting immunity assessment can help overcome many problems arising in gene therapy applications. Tackling such an urgent problem can expand the possibilities of therapy for many incurable human hereditary diseases.

Another challenge is the need to deeply understand the exact mechanisms and pathways of AAV cellular uptake, trafficking, and transduction, which are still unknown for most AAV serotypes. Such understanding can help in addressing and explaining the changes of transduction potency and efficacy that can be found between different species in different in vivo studies, or between treatment efficacy in vivo and in clinical trials. In other words, differences between humans and various animal models in terms of body size, genomic and anatomic specificity, immunogenicity, and disease process should be taken into account, as they can affect the effective translation of preclinical investigations.

7. Conclusions

AAVs were discovered over five decades ago and have since represented a potent tool for gene therapy, that still needs to be better understood and developed for broader and larger therapeutic applications. Further optimizations should cover vector design, tropism modifications, and delivery routes. In this article, we have covered different serotypes of adeno-associated viruses and their applications in gene therapy for different diseases in preclinical and clinical studies, with a brief overview of AAVs’ limitations and challenges.

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    Merten O.W., Gény-Fiamma C., Douar A.M. Current issues in adeno-associated viral vector production. Gene Ther. 2005;12((Suppl. S1)):S51-S61.

    Not in our library10.1038/sj.gt.3302615

  24. 24.

    Potter M., Lins B., Mietzsch M., Heilbronn R., Van Vliet K., Chipman P., Agbandje-McKenna M., Cleaver B.D., Clément N., Byrne B.J., et al. A simplified purification protocol for recombinant adeno-associated virus vectors. Mol. Ther. Methods Clin. Dev. 2014;1:14034.

    Not in our library10.1038/mtm.2014.34

  25. 25.

    Carter P.J., Samulski R.J. Adeno-associated viral vectors as gene delivery vehicles. Int. J. Mol. Med. 2000;6:17-27.

    Not in our library10.3892/ijmm.6.1.17

  26. 26.

    Cataldi M.P., McCarty D.M. Hairpin-end conformation of adeno-associated virus genome determines interactions with DNA-repair pathways. Gene Ther. 2013;20:686-693.

    Not in our library10.1038/gt.2012.86

  27. 27.

    Michelfelder S., Trepel M. Adeno-associated viral vectors and their redirection to cell-type specific receptors. Adv. Genet. 2009;67:29-60.

    Not in our library10.1016/s0065-2660(09)67002-4

  28. 28.

    Dubielzig R., King J.A., Weger S., Kern A., Kleinschmidt J.A. Adeno-associated virus type 2 protein interactions: Formation of pre-encapsidation complexes. J. Virol. 1999;73:8989-8998.

    Not in our library10.1128/jvi.73.11.8989-8998.1999

  29. 29.

    Kyöstiö S.R., Owens R.A., Weitzman M.D., Antoni B.A., Chejanovsky N., Carter B.J. Analysis of adeno-associated virus (AAV) wild-type and mutant Rep proteins for their abilities to negatively regulate AAV p5 and p19 mRNA levels. J. Virol. 1994;68:2947-2957.

    Not in our library10.1128/jvi.68.5.2947-2957.1994

  30. 30.

    Galibert L., Hyvönen A., Eriksson R.A.E., Mattola S., Aho V., Salminen S., Albers J.D., Peltola S.K., Weman S., Nieminen T., et al. Functional roles of the membrane-associated AAV protein MAAP. Sci. Rep. 2021;11:21698.

    Not in our library10.1038/s41598-021-01220-7

  31. 31.

    Kronenberg S., Kleinschmidt J.A., Böttcher B. Electron cryo-microscopy and image reconstruction of adeno-associated virus type 2 empty capsids. EMBO Rep. 2001;2:997-1002.

    Not in our library10.1093/embo-reports/kve234

  32. 32.

    Rabinowitz J.E., Samulski R.J. Building a better vector: The manipulation of AAV virions. Virology. 2000;278:301-308.

    Not in our library10.1006/viro.2000.0707

  33. 33.

    Wu Z., Asokan A., Samulski R.J. Adeno-associated virus serotypes: Vector toolkit for human gene therapy. Mol. Ther. J. Am. Soc. Gene Ther. 2006;14:316-327.

    Not in our library10.1016/j.ymthe.2006.05.009

  34. 34.

    Mori S., Wang L., Takeuchi T., Kanda T. Two novel adeno-associated viruses from cynomolgus monkey: Pseudotyping characterization of capsid protein. Virology. 2004;330:375-383.

    Not in our library10.1016/j.virol.2004.10.012

  35. 35.

    Gao G.P., Alvira M.R., Wang L., Calcedo R., Johnston J., Wilson J.M. Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc. Natl. Acad. Sci. USA. 2002;99:11854-11859.

    Not in our library10.1073/pnas.182412299

  36. 36.

    Wu Z., Miller E., Agbandje-McKenna M., Samulski R.J. Alpha2,3 and alpha2,6 N-linked sialic acids facilitate efficient binding and transduction by adeno-associated virus types 1 and 6. J. Virol. 2006;80:9093-9103.

    Not in our library10.1128/jvi.00895-06

  37. 37.

    Li C., Samulski R.J. Engineering adeno-associated virus vectors for gene therapy. Nat. Rev. Genet. 2020;21:255-272.

    Not in our library10.1038/s41576-019-0205-4

  38. 38.

    Rabinowitz J.E., Rolling F., Li C., Conrath H., Xiao W., Xiao X., Samulski R.J. Cross-packaging of a single adeno-associated virus (AAV) type 2 vector genome into multiple AAV serotypes enables transduction with broad specificity. J. Virol. 2002;76:791-801.

    Not in our library10.1128/jvi.76.2.791-801.2002

  39. 39.

    Zolotukhin S., Potter M., Zolotukhin I., Sakai Y., Loiler S., Fraites T.J., Chiodo V.A., Phillipsberg T., Muzyczka N., Hauswirth W.W., et al. Production and purification of serotype 1, 2, and 5 recombinant adeno-associated viral vectors. Methods. 2002;28:158-167.

    Not in our library10.1016/s1046-2023(02)00220-7

  40. 40.

    Robert M.A., Chahal P.S., Audy A., Kamen A., Gilbert R., Gaillet B. Manufacturing of recombinant adeno-associated viruses using mammalian expression platforms. Biotechnol. J. 2017;12:1600193.

    Not in our library10.1002/biot.201600193

  41. 41.

    Mary B., Maurya S., Arumugam S., Kumar V., Jayandharan G.R. Post-translational modifications in capsid proteins of recombinant adeno-associated virus (AAV) 1-rh10 serotypes. FEBS J. 2019;286:4964-4981.

    Not in our library10.1111/febs.15013

  42. 42.

    Huang L.-Y., Patel A., Ng R., Miller E.B., Halder S., McKenna R., Asokan A., Agbandje-McKenna M., Banks L. Characterization of the Adeno-Associated Virus 1 and 6 Sialic Acid Binding Site. J. Virol. 2016;90:5219-5230.

    Not in our library10.1128/jvi.00161-16

  43. 43.

    Chao H., Liu Y., Rabinowitz J., Li C., Samulski R.J., Walsh C.E. Several log increase in therapeutic transgene delivery by distinct adeno-associated viral serotype vectors. Mol. Ther. J. Am. Soc. Gene Ther. 2000;2:619-623.

    Not in our library10.1006/mthe.2000.0219

  44. 44.

    Hauck B., Xiao W. Characterization of tissue tropism determinants of adeno-associated virus type 1. J. Virol. 2003;77:2768-2774.

    Not in our library10.1128/jvi.77.4.2768-2774.2003

  45. 45.

    Lisowski L., Tay S.S., Alexander I.E. Adeno-associated virus serotypes for gene therapeutics. Curr. Opin. Pharmacol. 2015;24:59-67.

    Not in our library10.1016/j.coph.2015.07.006

  46. 46.

    Lu Y., Choi Y.K., Campbell-Thompson M., Li C., Tang Q., Crawford J.M., Flotte T.R., Song S. Therapeutic level of functional human alpha 1 antitrypsin (hAAT) secreted from murine muscle transduced by adeno-associated virus (rAAV1) vector. J. Gene Med. 2006;8:730-735.

    Not in our library10.1002/jgm.896

  47. 47.

    Wang C., Wang C.M., Clark K.R., Sferra T.J. Recombinant AAV serotype 1 transduction efficiency and tropism in the murine brain. Gene Ther. 2003;10:1528-1534.

    Not in our library10.1038/sj.gt.3302011

  48. 48.

    Su H., Yeghiazarians Y., Lee A., Huang Y., Arakawa-Hoyt J., Ye J., Orcino G., Grossman W., Kan Y.W. AAV serotype 1 mediates more efficient gene transfer to pig myocardium than AAV serotype 2 and plasmid. J. Gene Med. 2008;10:33-41.

    Not in our library10.1002/jgm.1129

  49. 49.

    Palomeque J., Chemaly E.R., Colosi P., Wellman J.A., Zhou S., Del Monte F., Hajjar R.J. Efficiency of eight different AAV serotypes in transducing rat myocardium in vivo. Gene Ther. 2007;14:989-997.

    Not in our library10.1038/sj.gt.3302895

  50. 50.

    Chen S., Kapturczak M., Loiler S.A., Zolotukhin S., Glushakova O.Y., Madsen K.M., Samulski R.J., Hauswirth W.W., Campbell-Thompson M., Berns K.I., et al. Efficient transduction of vascular endothelial cells with recombinant adeno-associated virus serotype 1 and 5 vectors. Hum. Gene Ther. 2005;16:235-247.

    Not in our library10.1089/hum.2005.16.235

  51. 51.

    Auricchio A., Kobinger G., Anand V., Hildinger M., O’Connor E., Maguire A.M., Wilson J.M., Bennett J. Exchange of surface proteins impacts on viral vector cellular specificity and transduction characteristics: The retina as a model. Hum. Mol. Genet. 2001;10:3075-3081.

    Not in our library10.1093/hmg/10.26.3075

  52. 52.

    Srivastava A. In vivo tissue-tropism of adeno-associated viral vectors. Curr. Opin. Virol. 2016;21:75-80.

    Not in our library10.1016/j.coviro.2016.08.003

  53. 53.

    Summerford C., Samulski R.J. Membrane-Associated Heparan Sulfate Proteoglycan Is a Receptor for Adeno-Associated Virus Type 2 Virions. J. Virol. 1998;72:1438-1445.

    Not in our library10.1128/jvi.72.2.1438-1445.1998

  54. 54.

    Opie S.R., Warrington K.H., Agbandje-McKenna M., Zolotukhin S., Muzyczka N. Identification of amino acid residues in the capsid proteins of adeno-associated virus type 2 that contribute to heparan sulfate proteoglycan binding. J. Virol. 2003;77:6995-7006.

    Not in our library10.1128/jvi.77.12.6995-7006.2003

  55. 55.

    Auricchio A., Sena-Esteves M., Gao G. Purification of Recombinant Adeno-Associated Virus 2 (rAAV2) by Heparin Column Affinity Chromatography. Cold Spring Harb. Protoc. 2020;2020:095620.

    Not in our library10.1101/pdb.prot095620

  56. 56.

    Qing K., Mah C., Hansen J., Zhou S., Dwarki V., Srivastava A.J. Human fibroblast growth factor receptor 1 is a co-receptor for infection by adeno-associated virus 2. Nat. Med. 1999;5:71-77.

    Not in our library10.1038/4758

  57. 57.

    Summerford C., Bartlett J.S., Samulski R.J.J. αVβ5 integrin: A co-receptor for adeno-associated virus type 2 infection. Nat. Med. 1999;5:78-82.

    Not in our library10.1038/4768

  58. 58.

    Asokan A., Hamra J.B., Govindasamy L., Agbandje-McKenna M., Samulski R.J.J. Adeno-associated virus type 2 contains an integrin α5β1 binding domain essential for viral cell entry. J. Virol. 2006;80:8961-8969.

    Not in our library10.1128/jvi.00843-06

  59. 59.

    Kashiwakura Y., Tamayose K., Iwabuchi K., Hirai Y., Shimada T., Matsumoto K., Nakamura T., Watanabe M., Oshimi K., Daida H.J. Hepatocyte growth factor receptor is a coreceptor for adeno-associated virus type 2 infection. J. Virol. 2005;79:609-614.

    Not in our library10.1128/jvi.79.1.609-614.2005

  60. 60.

    Akache B., Grimm D., Pandey K., Yant S.R., Xu H., Kay M.A.J. The 37/67-kilodalton laminin receptor is a receptor for adeno-associated virus serotypes 8, 2, 3, and 9. J. Virol. 2006;80:9831-9836.

    Not in our library10.1128/jvi.00878-06

  61. 61.

    Kurzeder C., Koppold B., Sauer G., Pabst S., Kreienberg R., Deissler H.J. CD9 promotes adeno-associated virus type 2 infection of mammary carcinoma cells with low cell surface expression of heparan sulphate proteoglycans. Int. J. Mol. Med. 2007;19:325-333.

    Not in our library10.3892/ijmm.19.2.325

  62. 62.

    Takeda S.-i., Takahashi M., Mizukami H., Kobayashi E., Takeuchi K., Hakamata Y., Kaneko T., Yamamoto H., Ito C., Ozawa K.J. Successful gene transfer using adeno-associated virus vectors into the kidney: Comparison among adeno-associated virus serotype 1–5 vectors in vitro and in vivo. Nephron Exp. Nephrol. 2004;96:e119-e126.

    Not in our library10.1159/000077378

  63. 63.

    Qi Y.F., Li Q.H., Shenoy V., Zingler M., Jun J.Y., Verma A., Katovich M.J., Raizada M.K. Comparison of the transduction efficiency of tyrosine-mutant adeno-associated virus serotype vectors in kidney. Clin. Exp. Pharmacol. Physiol. 2013;40:53-55.

    Not in our library10.1111/1440-1681.12037

  64. 64.

    Haddad G., Kölling M., Wegmann U.A., Dettling A., Seeger H., Schmitt R., Soerensen-Zender I., Haller H., Kistler A.D., Dueck A.J. Renal AAV2-mediated overexpression of long non-coding RNA H19 attenuates ischemic acute kidney injury through sponging of microRNA-30a-5p. J. Am. Soc. Nephrol. 2021;32:323-341.

    Not in our library10.1681/asn.2020060775

  65. 65.

    Logan G.J., Dane A.P., Hallwirth C.V., Smyth C.M., Wilkie E.E., Amaya A.K., Zhu E., Khandekar N., Ginn S.L., Liao S.H. Identification of liver-specific enhancer–promoter activity in the 3′ untranslated region of the wild-type AAV2 genome. Nat. Genet. 2017;49:1267-1273.

    Not in our library10.1038/ng.3893

  66. 66.

    Niemeyer G.P., Herzog R.W., Mount J., Arruda V.R., Tillson D.M., Hathcock J., van Ginkel F.W., High K.A., Lothrop C.D. The Journal of the American Society of Hematology. Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy. Blood J. Am. Soc. Hematol. 2009;113:797-806.

    Not in our library10.1182/blood-2008-10-181479

  67. 67.

    Petrs-Silva H., Dinculescu A., Li Q., Deng W.-T., Pang J.-j., Min S.-H., Chiodo V., Neeley A.W., Govindasamy L., Bennett A., et al. Novel Properties of Tyrosine-mutant AAV2 Vectors in the Mouse Retina. Mol. Ther. 2011;19:293-301.

    Not in our library10.1038/mt.2010.234

  68. 68.

    Yin L., Greenberg K., Hunter J.J., Dalkara D., Kolstad K.D., Masella B.D., Wolfe R., Visel M., Stone D., Libby R.T., et al. Intravitreal injection of AAV2 transduces macaque inner retina. Investig. Ophthalmol. Vis. Sci. 2011;52:2775-2783.

    Not in our library10.1167/iovs.10-6250

  69. 69.
    Exosome-associated AAV2 vector mediates robust gene delivery into the murine retina upon intravitreal injection · 2017
    No notice
  70. 70.

    Griffey M., Bible E., Vogler C., Levy B., Gupta P., Cooper J., Sands M.S. Adeno-associated virus 2-mediated gene therapy decreases autofluorescent storage material and increases brain mass in a murine model of infantile neuronal ceroid lipofuscinosis. Neurobiol. Dis. 2004;16:360-369.

    Not in our library10.1016/j.nbd.2004.03.005

  71. 71.

    Griffey M.A., Wozniak D., Wong M., Bible E., Johnson K., Rothman S.M., Wentz A.E., Cooper J.D., Sands M.S. CNS-directed AAV2-mediated gene therapy ameliorates functional deficits in a murine model of infantile neuronal ceroid lipofuscinosis. Mol. Ther. 2006;13:538-547.

    Not in our library10.1016/j.ymthe.2005.11.008

  72. 72.

    Pankajakshan D., Makinde T.O., Gaurav R., Del Core M., Hatzoudis G., Pipinos I., Agrawal D.K. Successful Transfection of Genes Using AAV-2/9 Vector in Swine Coronary and Peripheral Arteries. J. Surg. Res. 2012;175:169-175.

    Not in our library10.1016/j.jss.2011.02.032

  73. 73.

    Rabinowitz J.E., Bowles D.E., Faust S.M., Ledford J.G., Cunningham S.E., Samulski R.J. Cross-Dressing the Virion: The Transcapsidation of Adeno-Associated Virus Serotypes Functionally Defines Subgroups. J. Virol. 2004;78:4421-4432.

    Not in our library10.1128/jvi.78.9.4421-4432.2004

  74. 74.

    Blackburn S.D., Steadman R.A., Johnson F.B. Attachment of adeno-associated virus type 3H to fibroblast growth factor receptor 1. Arch. Virol. 2006;151:617-623.

    Not in our library10.1007/s00705-005-0650-6

  75. 75.

    Ling C., Wang Y., Zhang Y., Ejjigani A., Yin Z., Lu Y., Wang L., Wang M., Li J., Hu Z., et al. Selective in vivo targeting of human liver tumors by optimized AAV3 vectors in a murine xenograft model. Hum. Gene Ther. 2014;25:1023-1034.

    Not in our library10.1089/hum.2014.099

  76. 76.

    Ling C., Yin Z., Li J., Zhang D., Aslanidi G., Srivastava A. Strategies to generate high-titer, high-potency recombinant AAV3 serotype vectors. Mol. Ther. Methods Clin. Dev. 2016;3:16029.

    Not in our library10.1038/mtm.2016.29

  77. 77.

    Handa A., Muramatsu S.I., Qiu J., Mizukami H., Brown K.E. Adeno-associated virus (AAV)-3-based vectors transduce haematopoietic cells not susceptible to transduction with AAV-2-based vectors. J. Gen. Virol. 2000;81:2077-2084.

    Not in our library10.1099/0022-1317-81-8-2077

  78. 78.

    Cheng B., Ling C., Dai Y., Lu Y., Glushakova L.G., Gee S.W.Y., McGoogan K.E., Aslanidi G.V., Park M., Stacpoole P.W., et al. Development of optimized AAV3 serotype vectors: Mechanism of high-efficiency transduction of human liver cancer cells. Gene Ther. 2012;19:375-384.

    Not in our library10.1038/gt.2011.105

  79. 79.

    Muramatsu S., Mizukami H., Young N.S., Brown K.E. Nucleotide sequencing and generation of an infectious clone of adeno-associated virus 3. Virology. 1996;221:208-217.

    Not in our library10.1006/viro.1996.0367

  80. 80.

    Li S., Ling C., Zhong L., Li M., Su Q., He R., Tang Q., Greiner D.L., Shultz L.D., Brehm M.A., et al. Efficient and Targeted Transduction of Nonhuman Primate Liver With Systemically Delivered Optimized AAV3B Vectors. Mol. Ther. 2015;23:1867-1876.

    Not in our library10.1038/mt.2015.174

  81. 81.

    Vercauteren K., Hoffman B.E., Zolotukhin I., Keeler G.D., Xiao J.W., Basner-Tschakarjan E., High K.A., Ertl H.C.J., Rice C.M., Srivastava A., et al. Superior In vivo Transduction of Human Hepatocytes Using Engineered AAV3 Capsid. Mol. Ther. 2016;24:1042-1049.

    Not in our library10.1038/mt.2016.61

  82. 82.

    Liu Y., Okada T., Sheykholeslami K., Shimazaki K., Nomoto T., Muramatsu S., Kanazawa T., Takeuchi K., Ajalli R., Mizukami H., et al. Specific and efficient transduction of Cochlear inner hair cells with recombinant adeno-associated virus type 3 vector. Mol. Ther. J. Am. Soc. Gene Ther. 2005;12:725-733.

    Not in our library10.1016/j.ymthe.2005.03.021

  83. 83.

    Padron E., Bowman V., Kaludov N., Govindasamy L., Levy H., Nick P., McKenna R., Muzyczka N., Chiorini J.A., Baker T.S., et al. Structure of adeno-associated virus type 4. J. Virol. 2005;79:5047-5058.

    Not in our library10.1128/jvi.79.8.5047-5058.2005

  84. 84.

    Parks W.P., Boucher D.W., Melnick J.L., Taber L.H., Yow M.D. Seroepidemiological and ecological studies of the adenovirus-associated satellite viruses. Infect. Immun. 1970;2:716-722.

    Not in our library10.1128/iai.2.6.716-722.1970

  85. 85.

    Blacklow N.R., Hoggan M.D., Rowe W.P. Serologic evidence for human infection with adenovirus-associated viruses. J. Natl. Cancer Inst. 1968;40:319-327.

    Not in our library

  86. 86.

    Dreizin R.S., Zhuravel T.F., Tarasova A.B., Sobolev S.G., Kozlov V.G. Experimental infection of green monkeys with adenoassociated virus. Vopr. Virusol. 1981;1:82-89.

    Not in our library

  87. 87.

    Chiorini J.A., Yang L., Liu Y., Safer B., Kotin R.M. Cloning of adeno-associated virus type 4 (AAV4) and generation of recombinant AAV4 particles. J. Virol. 1997;71:6823-6833.

    Not in our library10.1128/jvi.71.9.6823-6833.1997

  88. 88.

    Kaludov N., Brown K.E., Walters R.W., Zabner J., Chiorini J.A. Adeno-associated virus serotype 4 (AAV4) and AAV5 both require sialic acid binding for hemagglutination and efficient transduction but differ in sialic acid linkage specificity. J. Virol. 2001;75:6884-6893.

    Not in our library10.1128/jvi.75.15.6884-6893.2001

  89. 89.

    Kaludov N., Handelman B., Chiorini J.A. Scalable purification of adeno-associated virus type 2, 4, or 5 using ion-exchange chromatography. Hum. Gene Ther. 2002;13:1235-1243.

    Not in our library10.1089/104303402320139014

  90. 90.
    Recombinant adeno-associated virus type 2, 4, and 5 vectors: Transduction of variant cell types and regions in the mammalian central nervous system · 2000
    Not checked
  91. 91.

    Weber M., Rabinowitz J., Provost N., Conrath H., Folliot S., Briot D., Chérel Y., Chenuaud P., Samulski J., Moullier P., et al. Recombinant adeno-associated virus serotype 4 mediates unique and exclusive long-term transduction of retinal pigmented epithelium in rat, dog, and nonhuman primate after subretinal delivery. Mol. Ther. J. Am. Soc. Gene Ther. 2003;7:774-781.

    Not in our library10.1016/s1525-0016(03)00098-4

  92. 92.

    Zincarelli C., Soltys S., Rengo G., Rabinowitz J.E. Analysis of AAV serotypes 1–9 mediated gene expression and tropism in mice after systemic injection. Mol. Ther. 2008;16:1073-1080.

    Not in our library10.1038/mt.2008.76

  93. 93.

    Bantel-Schaal U., zur Hausen H. Characterization of the DNA of a defective human parvovirus isolated from a genital site. Virology. 1984;134:52-63.

    Not in our library10.1016/0042-6822(84)90271-x

  94. 94.

    Stutika C., Hüser D., Weger S., Rutz N., Heßler M., Heilbronn R. Definition of herpes simplex virus helper functions for the replication of adeno-associated virus type 5. J. Gen. Virol. 2015;96:840-850.

    Not in our library10.1099/vir.0.000034

  95. 95.

    Bantel-Schaal U., Delius H., Schmidt R., Hausen H.Z. Human Adeno-Associated Virus Type 5 Is Only Distantly Related to Other Known Primate Helper-Dependent Parvoviruses. J. Virol. 1999;73:939-947.

    Not in our library10.1128/jvi.73.2.939-947.1999

  96. 96.

    Chiorini J.A., Kim F., Yang L., Kotin R.M. Cloning and characterization of adeno-associated virus type 5. J. Virol. 1999;73:1309-1319.

    Not in our library10.1128/jvi.73.2.1309-1319.1999

  97. 97.

    Bantel-Schaal U., Hub B., Kartenbeck J. Endocytosis of adeno-associated virus type 5 leads to accumulation of virus particles in the Golgi compartment. J. Virol. 2002;76:2340-2349.

    Not in our library10.1128/jvi.76.5.2340-2349.2002

  98. 98.

    Zabner J., Seiler M., Walters R., Kotin R.M., Fulgeras W., Davidson B.L., Chiorini J.A. Adeno-associated virus type 5 (AAV5) but not AAV2 binds to the apical surfaces of airway epithelia and facilitates gene transfer. J. Virol. 2000;74:3852-3858.

    Not in our library10.1128/jvi.74.8.3852-3858.2000

  99. 99.

    Grimm D., Kay M.A. From virus evolution to vector revolution: Use of naturally occurring serotypes of adeno-associated virus (AAV) as novel vectors for human gene therapy. Curr. Gene Ther. 2003;3:281-304.

    Not in our library10.2174/1566523034578285

  100. 100.

    Walters R.W., Yi S.M., Keshavjee S., Brown K.E., Welsh M.J., Chiorini J.A., Zabner J. Binding of adeno-associated virus type 5 to 2,3-linked sialic acid is required for gene transfer. J. Biol. Chem. 2001;276:20610-20616.

    Not in our library10.1074/jbc.m101559200

  101. 101.

    Henckaerts E., Linden R.M. Adeno-associated virus: A key to the human genome? Future Virol. 2010;5:555-574.

    Not in our library10.2217/fvl.10.48

  102. 102.

    Di Pasquale G., Davidson B.L., Stein C.S., Martins I., Scudiero D., Monks A., Chiorini J.A. Identification of PDGFR as a receptor for AAV-5 transduction. Nat. Med. 2003;9:1306-1312.

    Not in our library10.1038/nm929

  103. 103.

    Nonnenmacher M., Weber T. Intracellular transport of recombinant adeno-associated virus vectors. Gene Ther. 2012;19:649-658.

    Not in our library10.1038/gt.2012.6

  104. 104.

    Auricchio A., O’Connor E., Hildinger M., Wilson J.M. A Single-Step Affinity Column for Purification of Serotype-5 Based Adeno-associated Viral Vectors. Mol. Ther. 2001;4:372-374.

    Not in our library10.1006/mthe.2001.0462

  105. 105.

    Walters R.W., Pilewski J.M., Chiorini J.A., Zabner J. Secreted and Transmembrane Mucins Inhibit Gene Transfer with AAV4 More Efficiently than AAV5*. J. Biol. Chem. 2002;277:23709-23713.

    Not in our library10.1074/jbc.m200292200

  106. 106.

    Yang G.S., Schmidt M., Yan Z., Lindbloom J.D., Harding T.C., Donahue B.A., Engelhardt J.F., Kotin R., Davidson B.L. Virus-mediated transduction of murine retina with adeno-associated virus: Effects of viral capsid and genome size. J. Virol. 2002;76:7651-7660.

    Not in our library10.1128/jvi.76.15.7651-7660.2002

  107. 107.

    Alisky J.M., Hughes S.M., Sauter S.L., Jolly D., Dubensky T.W., Staber P.D., Chiorini J.A., Davidson B.L. Transduction of murine cerebellar neurons with recombinant FIV and AAV5 vectors. Neuroreport. 2000;11:2669-2673.

    Not in our library10.1097/00001756-200008210-00013

  108. 108.

    Burger C., Gorbatyuk O.S., Velardo M.J., Peden C.S., Williams P., Zolotukhin S., Reier P.J., Mandel R.J., Muzyczka N. Recombinant AAV viral vectors pseudotyped with viral capsids from serotypes 1, 2, and 5 display differential efficiency and cell tropism after delivery to different regions of the central nervous system. Mol. Ther. J. Am. Soc. Gene Ther. 2004;10:302-317.

    Not in our library10.1016/j.ymthe.2004.05.024

  109. 109.

    Ding W., Yan Z., Zak R., Saavedra M., Rodman D.M., Engelhardt J.F. Second-strand genome conversion of adeno-associated virus type 2 (AAV-2) and AAV-5 is not rate limiting following apical infection of polarized human airway epithelia. J. Virol. 2003;77:7361-7366.

    Not in our library10.1128/jvi.77.13.7361-7366.2003

  110. 110.

    Auricchio A., O’Connor E., Weiner D., Gao G.P., Hildinger M., Wang L., Calcedo R., Wilson J.M. Noninvasive gene transfer to the lung for systemic delivery of therapeutic proteins. J. Clin. Investig. 2002;110:499-504.

    Not in our library10.1172/jci0215780

  111. 111.

    Seiler M.P., Miller A.D., Zabner J., Halbert C.L. Adeno-associated virus types 5 and 6 use distinct receptors for cell entry. Hum. Gene Ther. 2006;17:10-19.

    Not in our library10.1089/hum.2006.17.10

  112. 112.

    Pañeda A., Vanrell L., Mauleon I., Crettaz J.S., Berraondo P., Timmermans E.J., Beattie S.G., Twisk J., van Deventer S., Prieto J., et al. Effect of adeno-associated virus serotype and genomic structure on liver transduction and biodistribution in mice of both genders. Hum. Gene Ther. 2009;20:908-917.

    Not in our library10.1089/hum.2009.031

  113. 113.

    Xiao W., Chirmule N., Berta S.C., McCullough B., Gao G., Wilson J.M. Gene Therapy Vectors Based on Adeno-Associated Virus Type 1. J. Virol. 1999;73:3994-4003.

    Not in our library10.1128/jvi.73.5.3994-4003.1999

  114. 114.

    Rutledge E.A., Halbert C.L., Russell D.W. Infectious Clones and Vectors Derived from Adeno-Associated Virus (AAV) Serotypes Other Than AAV Type 2. J. Virol. 1998;72:309-319.

    Not in our library10.1128/jvi.72.1.309-319.1998

  115. 115.

    Korneyenkov M.A., Zamyatnin A.A. Next Step in Gene Delivery: Modern Approaches and Further Perspectives of AAV Tropism Modification. Pharmaceutics. 2021;13:750.

    Not in our library10.3390/pharmaceutics13050750

  116. 116.

    Ng R., Govindasamy L., Gurda B.L., McKenna R., Kozyreva O.G., Samulski R.J., Parent K.N., Baker T.S., Agbandje-McKenna M. Structural characterization of the dual glycan binding adeno-associated virus serotype 6. J. Virol. 2010;84:12945-12957.

    Not in our library10.1128/jvi.01235-10

  117. 117.

    Wu Z., Asokan A., Grieger J.C., Govindasamy L., Agbandje-McKenna M., Samulski R.J. Single amino acid changes can influence titer, heparin binding, and tissue tropism in different adeno-associated virus serotypes. J. Virol. 2006;80:11393-11397.

    Not in our library10.1128/jvi.01288-06

  118. 118.

    Weller M.L., Amornphimoltham P., Schmidt M., Wilson P.A., Gutkind J.S., Chiorini J.A. Epidermal growth factor receptor is a co-receptor for adeno-associated virus serotype 6. Nat. Med. 2010;16:662-664.

    Not in our library10.1038/nm.2145

  119. 119.

    Halbert C.L., Allen J.M., Miller A.D. Adeno-associated virus type 6 (AAV6) vectors mediate efficient transduction of airway epithelial cells in mouse lungs compared to that of AAV2 vectors. J. Virol. 2001;75:6615-6624.

    Not in our library10.1128/jvi.75.14.6615-6624.2001

  120. 120.

    Halbert C.L., Madtes D.K., Vaughan A.E., Wang Z., Storb R., Tapscott S.J., Miller A.D. Expression of human alpha1-antitrypsin in mice and dogs following AAV6 vector-mediated gene transfer to the lungs. Mol. Ther. J. Am. Soc. Gene Ther. 2010;18:1165-1172.

    Not in our library10.1038/mt.2010.51

  121. 121.

    Grimm D., Zhou S., Nakai H., Thomas C.E., Storm T.A., Fuess S., Matsushita T., Allen J., Surosky R., Lochrie M., et al. Preclinical in vivo evaluation of pseudotyped adeno-associated virus vectors for liver gene therapy. Blood. 2003;102:2412-2419.

    Not in our library10.1182/blood-2003-02-0495

  122. 122.

    Blankinship M.J., Gregorevic P., Allen J.M., Harper S.Q., Harper H., Halbert C.L., Miller A.D., Chamberlain J.S. Efficient transduction of skeletal muscle using vectors based on adeno-associated virus serotype 6. Mol. Ther. J. Am. Soc. Gene Ther. 2004;10:671-678.

    Not in our library10.1016/j.ymthe.2004.07.016

  123. 123.

    Wang Z., Kuhr C.S., Allen J.M., Blankinship M., Gregorevic P., Chamberlain J.S., Tapscott S.J., Storb R. Sustained AAV-mediated dystrophin expression in a canine model of Duchenne muscular dystrophy with a brief course of immunosuppression. Mol. Ther. J. Am. Soc. Gene Ther. 2007;15:1160-1166.

    Not in our library10.1038/sj.mt.6300161

  124. 124.

    Qiao C., Zhang W., Yuan Z., Shin J.H., Li J., Jayandharan G.R., Zhong L., Srivastava A., Xiao X., Duan D. Adeno-associated virus serotype 6 capsid tyrosine-to-phenylalanine mutations improve gene transfer to skeletal muscle. Hum. Gene Ther. 2010;21:1343-1348.

    Not in our library10.1089/hum.2010.003

  125. 125.

    Zincarelli C., Soltys S., Rengo G., Koch W.J., Rabinowitz J.E. Comparative cardiac gene delivery of adeno-associated virus serotypes 1–9 reveals that AAV6 mediates the most efficient transduction in mouse heart. Clin. Transl. Sci. 2010;3:81-89.

    Not in our library10.1111/j.1752-8062.2010.00190.x

  126. 126.

    Raake P.W., Hinkel R., Müller S., Delker S., Kreuzpointner R., Kupatt C., Katus H.A., Kleinschmidt J.A., Boekstegers P., Müller O.J. Cardio-specific long-term gene expression in a porcine model after selective pressure-regulated retroinfusion of adeno-associated viral (AAV) vectors. Gene Ther. 2008;15:12-17.

    Not in our library10.1038/sj.gt.3303035

  127. 127.

    Bish L.T., Sleeper M.M., Reynolds C., Gazzara J., Withnall E., Singletary G.E., Buchlis G., Hui D., High K.A., Gao G., et al. Cardiac gene transfer of short hairpin RNA directed against phospholamban effectively knocks down gene expression but causes cellular toxicity in canines. Hum. Gene Ther. 2011;22:969-977.

    Not in our library10.1089/hum.2011.035

  128. 128.

    White J.D., Thesier D.M., Swain J.B., Katz M.G., Tomasulo C., Henderson A., Wang L., Yarnall C., Fargnoli A., Sumaroka M., et al. Myocardial gene delivery using molecular cardiac surgery with recombinant adeno-associated virus vectors in vivo. Gene Ther. 2011;18:546-552.

    Not in our library10.1038/gt.2010.168

  129. 129.

    Gao G., Vandenberghe L.H., Alvira M.R., Lu Y., Calcedo R., Zhou X., Wilson J.M. Clades of Adeno-associated viruses are widely disseminated in human tissues. J. Virol. 2004;78:6381-6388.

    Not in our library10.1128/jvi.78.12.6381-6388.2004

  130. 130.

    Denby L., Nicklin S.A., Baker A.H. Adeno-associated virus (AAV)-7 and -8 poorly transduce vascular endothelial cells and are sensitive to proteasomal degradation. Gene Ther. 2005;12:1534-1538.

    Not in our library10.1038/sj.gt.3302564

  131. 131.

    Mietzsch M., Broecker F., Reinhardt A., Seeberger P.H., Heilbronn R. Differential Adeno-Associated Virus Serotype-Specific Interaction Patterns with Synthetic Heparins and Other Glycans. J. Virol. 2014;88:2991-3003.

    Not in our library10.1128/jvi.03371-13

  132. 132.

    Calcedo R., Vandenberghe L.H., Gao G., Lin J., Wilson J.M. Worldwide Epidemiology of Neutralizing Antibodies to Adeno-Associated Viruses. J. Infect. Dis. 2009;199:381-390.

    Not in our library10.1086/595830

  133. 133.

    Louboutin J.-P., Wang L., Wilson J.M. Gene transfer into skeletal muscle using novel AAV serotypes. J. Gene Med. A Cross-Discip. J. Res. Sci. Gene Transf. Clin. Appl. 2005;7:442-451.

    Not in our library10.1002/jgm.686

  134. 134.

    Samaranch L., Salegio E.A., San Sebastian W., Kells A.P., Bringas J.R., Forsayeth J., Bankiewicz K.S. Strong cortical and spinal cord transduction after AAV7 and AAV9 delivery into the cerebrospinal fluid of nonhuman primates. Hum. Gene Ther. 2013;24:526-532.

    Not in our library10.1089/hum.2013.005

  135. 135.

    Taymans J.M., Vandenberghe L.H., Haute C.V., Thiry I., Deroose C.M., Mortelmans L., Wilson J.M., Debyser Z., Baekelandt V. Comparative analysis of adeno-associated viral vector serotypes 1, 2, 5, 7, and 8 in mouse brain. Hum. Gene Ther. 2007;18:195-206.

    Not in our library10.1089/hum.2006.178

  136. 136.

    Allocca M., Mussolino C., Garcia-Hoyos M., Sanges D., Iodice C., Petrillo M., Vandenberghe L.H., Wilson J.M., Marigo V., Surace E.M., et al. Novel adeno-associated virus serotypes efficiently transduce murine photoreceptors. J. Virol. 2007;81:11372-11380.

    Not in our library10.1128/jvi.01327-07

  137. 137.

    Okada T., Nonaka-Sarukawa M., Uchibori R., Kinoshita K., Hayashita-Kinoh H., Nitahara-Kasahara Y., Takeda S.i., Ozawa K. Scalable purification of adeno-associated virus serotype 1 (AAV1) and AAV8 vectors, using dual ion-exchange adsorptive membranes. Hum. Gene Ther. 2009;20:1013-1021.

    Not in our library10.1089/hum.2009.006

  138. 138.

    Davidoff A.M., Ng C.Y., Sleep S., Gray J., Azam S., Zhao Y., McIntosh J.H., Karimipoor M., Nathwani A.C. Purification of recombinant adeno-associated virus type 8 vectors by ion exchange chromatography generates clinical grade vector stock. J. Virol. Methods. 2004;121:209-215.

    Not in our library10.1016/j.jviromet.2004.07.001

  139. 139.

    Lane M.D., Nam H.-J., Padron E., Gurda-Whitaker B., Kohlbrenner E., Aslanidi G., Byrne B., McKenna R., Muzyczka N., Zolotukhin S., et al. Production, purification, crystallization and preliminary X-ray analysis of adeno-associated virus serotype 8. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 2005;61:558-561.

    Not in our library10.1107/s1744309105014132

  140. 140.

    Miyake K., Miyake N., Yamazaki Y., Shimada T., Hirai Y.J. Serotype-independent method of recombinant adeno-associated virus (AAV) vector production and purification. J. Nippon. Med. Sch. 2012;79:394-402.

    Not in our library10.1272/jnms.79.394

  141. 141.

    Nam H.-J., Lane M.D., Padron E., Gurda B., McKenna R., Kohlbrenner E., Aslanidi G., Byrne B., Muzyczka N., Zolotukhin S., et al. Structure of Adeno-Associated Virus Serotype 8, a Gene Therapy Vector. J. Virol. 2007;81:12260-12271.

    Not in our library10.1128/jvi.01304-07

  142. 142.

    Cabanes-Creus M., Navarro R.G., Zhu E., Baltazar G., Liao S.H.Y., Drouyer M., Amaya A.K., Scott S., Nguyen L.H., Westhaus A., et al. Novel human liver-tropic AAV variants define transferable domains that markedly enhance the human tropism of AAV7 and AAV8. Mol. Ther. Methods Clin. Dev. 2022;24:88-101.

    Not in our library10.1016/j.omtm.2021.11.011

  143. 143.

    Nakai H., Fuess S., Storm T.A., Muramatsu S., Nara Y., Kay M.A. Unrestricted hepatocyte transduction with adeno-associated virus serotype 8 vectors in mice. J. Virol. 2005;79:214-224.

    Not in our library10.1128/jvi.79.1.214-224.2005

  144. 144.

    Thomas C.E., Storm T.A., Huang Z., Kay M.A. Rapid uncoating of vector genomes is the key to efficient liver transduction with pseudotyped adeno-associated virus vectors. J. Virol. 2004;78:3110-3122.

    Not in our library10.1128/jvi.78.6.3110-3122.2004

  145. 145.

    Nam H.-J., Gurda B.L., McKenna R., Potter M., Byrne B., Salganik M., Muzyczka N., Agbandje-McKenna M. Structural Studies of Adeno-Associated Virus Serotype 8 Capsid Transitions Associated with Endosomal Trafficking. J. Virol. 2011;85:11791-11799.

    Not in our library10.1128/jvi.05305-11

  146. 146.

    Monahan P.E., Lothrop C.D., Sun J., Hirsch M.L., Kafri T., Kantor B., Sarkar R., Tillson D.M., Elia J.R., Samulski R.J. Proteasome inhibitors enhance gene delivery by AAV virus vectors expressing large genomes in hemophilia mouse and dog models: A strategy for broad clinical application. Mol. Ther. J. Am. Soc. Gene Ther. 2010;18:1907-1916.

    Not in our library10.1038/mt.2010.170

  147. 147.

    Jiang H., Couto L.B., Patarroyo-White S., Liu T., Nagy D., Vargas J.A., Zhou S., Scallan C.D., Sommer J., Vijay S., et al. Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy. Blood. 2006;108:3321-3328.

    Not in our library10.1182/blood-2006-04-017913

  148. 148.

    Wang Z., Zhu T., Qiao C., Zhou L., Wang B., Zhang J., Chen C., Li J., Xiao X. Adeno-associated virus serotype 8 efficiently delivers genes to muscle and heart. Nat. Biotechnol. 2005;23:321-328.

    Not in our library10.1038/nbt1073

  149. 149.

    Wang A.Y., Peng P.D., Ehrhardt A., Storm T.A., Kay M.A. Comparison of adenoviral and adeno-associated viral vectors for pancreatic gene delivery in vivo. Hum. Gene Ther. 2004;15:405-413.

    Not in our library10.1089/104303404322959551

  150. 150.

    Loiler S.A., Tang Q., Clarke T., Campbell-Thompson M.L., Chiodo V., Hauswirth W., Cruz P., Perret-Gentil M., Atkinson M.A., Ramiya V.K., et al. Localized gene expression following administration of adeno-associated viral vectors via pancreatic ducts. Mol. Ther. J. Am. Soc. Gene Ther. 2005;12:519-527.

    Not in our library10.1016/j.ymthe.2005.04.017

  151. 151.

    Rubin J.D., Nguyen T.V., Allen K.L., Ayasoufi K., Barry M.A. Comparison of gene delivery to the kidney by adenovirus, adeno-associated virus, and lentiviral vectors after intravenous and direct kidney injections. Hum. Gene Ther. 2019;30:1559-1571.

    Not in our library10.1089/hum.2019.127

  152. 152.

    Giove T.J., Khankhel Z.S., Sena-Esteves M., Eldred W.D. Cellular Tropism of Aav8, Aav9 and Aav10 in Mouse Retina. Investig. Ophthalmol. Vis. Sci. 2009;50:3013.

    Not in our library

  153. 153.

    Ding K., Shen J., Hafiz Z., Hackett S.F., Silva R.L.E., Khan M., Lorenc V.E., Chen D., Chadha R., Zhang M., et al. AAV8-vectored suprachoroidal gene transfer produces widespread ocular transgene expression. J. Clin. Investig. 2019;129:4901-4911.

    Not in our library10.1172/jci129085

  154. 154.

    Igarashi T., Miyake K., Asakawa N., Miyake N., Shimada T., Takahashi H. Direct Comparison of Administration Routes for AAV8-mediated Ocular Gene Therapy. Curr. Eye Res. 2013;38:569-577.

    Not in our library10.3109/02713683.2013.779720

  155. 155.

    Gao G., Vandenberghe L.H., Wilson J.M. New recombinant serotypes of AAV vectors. Curr. Gene Ther. 2005;5:285-297.

    Not in our library10.2174/1566523054065057

  156. 156.

    Shen S., Bryant K.D., Brown S.M., Randell S.H., Asokan A. Terminal N-Linked Galactose Is the Primary Receptor for Adeno-associated Virus 9*. J. Biol. Chem. 2011;286:13532-13540.

    Not in our library10.1074/jbc.m110.210922

  157. 157.

    Bell C.L., Gurda B.L., Van Vliet K., Agbandje-McKenna M., Wilson J.M. Identification of the galactose binding domain of the adeno- associated virus serotype 9 capsid. J. Virol. 2012;86:7326-7333.

    Not in our library10.1128/jvi.00448-12

  158. 158.

    Mitchell M., Nam H.-J., Carter A., McCall A., Rence C., Bennett A., Gurda B., McKenna R., Porter M., Sakai Y., et al. Production, purification and preliminary X-ray crystallographic studies of adeno-associated virus serotype 9. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 2009;65:715-718.

    Not in our library10.1107/s1744309109021460

  159. 159.

    Foust K.D., Nurre E., Montgomery C.L., Hernandez A., Chan C.M., Kaspar B.K. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat. Biotechnol. 2009;27:59-65.

    Not in our library10.1038/nbt.1515

  160. 160.

    Gray S.J., Matagne V., Bachaboina L., Yadav S., Ojeda S.R., Samulski R.J. Preclinical Differences of Intravascular AAV9 Delivery to Neurons and Glia: A Comparative Study of Adult Mice and Nonhuman Primates. Mol. Ther. 2011;19:1058-1069.

    Not in our library10.1038/mt.2011.72

  161. 161.

    Bevan A.K., Duque S., Foust K.D., Morales P.R., Braun L., Schmelzer L., Chan C.M., McCrate M., Chicoine L.G., Coley B.D., et al. Systemic Gene Delivery in Large Species for Targeting Spinal Cord, Brain, and Peripheral Tissues for Pediatric Disorders. Mol. Ther. 2011;19:1971-1980.

    Not in our library10.1038/mt.2011.157

  162. 162.

    Duque S., Joussemet B., Riviere C., Marais T., Dubreil L., Douar A.M., Fyfe J., Moullier P., Colle M.A., Barkats M. Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol. Ther. J. Am. Soc. Gene Ther. 2009;17:1187-1196.

    Not in our library10.1038/mt.2009.71

  163. 163.

    Vandenberghe L.H., Bell P., Maguire A.M., Xiao R., Hopkins T.B., Grant R., Bennett J., Wilson J.M., Xiao X. AAV9 targets cone photoreceptors in the nonhuman primate retina. PLoS ONE. 2013;8:e53463.

    Not in our library10.1371/annotation/64b90996-4634-4c63-b737-634397b0b445

  164. 164.

    Pacak C.A., Mah C.S., Thattaliyath B.D., Conlon T.J., Lewis M.A., Cloutier D.E., Zolotukhin I., Tarantal A.F., Byrne B.J. Recombinant adeno-associated virus serotype 9 leads to preferential cardiac transduction in vivo. Circ. Res. 2006;99:e3-e9.

    Not in our library10.1161/01.res.0000237661.18885.f6

  165. 165.

    Asokan A., Schaffer D.V., Samulski R.J. The AAV vector toolkit: Poised at the clinical crossroads. Mol. Ther. 2012;20:699-708.

    Not in our library10.1038/mt.2011.287

  166. 166.

    Pleger S.T., Shan C., Ksienzyk J., Bekeredjian R., Boekstegers P., Hinkel R., Schinkel S., Leuchs B., Ludwig J., Qiu G. Cardiac AAV9-S100A1 gene therapy rescues post-ischemic heart failure in a preclinical large animal model. Sci. Transl. Med. 2011;3:92ra64.

    Not in our library10.1126/scitranslmed.3002097

  167. 167.

    Bish L.T., Morine K., Sleeper M.M., Sanmiguel J., Wu D., Gao G., Wilson J.M., Sweeney H.L. Adeno-associated virus (AAV) serotype 9 provides global cardiac gene transfer superior to AAV1, AAV6, AAV7, and AAV8 in the mouse and rat. Hum. Gene Ther. 2008;19:1359-1368.

    Not in our library10.1089/hum.2008.123

  168. 168.

    Vandendriessche T., Thorrez L., Acosta-Sanchez A., Petrus I., Wang L., Ma L., De Waele L., Iwasaki Y., Gillijns V., Wilson J.M., et al. Efficacy and safety of adeno-associated viral vectors based on serotype 8 and 9 vs. lentiviral vectors for hemophilia B gene therapy. J. Thromb. Haemost. JTH. 2007;5:16-24.

    Not in our library10.1111/j.1538-7836.2006.02220.x

  169. 169.

    Inagaki K., Fuess S., Storm T.A., Gibson G.A., McTiernan C.F., Kay M.A., Nakai H. Robust systemic transduction with AAV9 vectors in mice: Efficient global cardiac gene transfer superior to that of AAV8. Mol. Ther. J. Am. Soc. Gene Ther. 2006;14:45-53.

    Not in our library10.1016/j.ymthe.2006.03.014

  170. 170.

    Petrs-Silva H., Dinculescu A., Li Q., Min S.-H., Chiodo V., Pang J.-J., Zhong L., Zolotukhin S., Srivastava A., Lewin A.S., et al. High-efficiency Transduction of the Mouse Retina by Tyrosine-mutant AAV Serotype Vectors. Mol. Ther. 2009;17:463-471.

    Not in our library10.1038/mt.2008.269

  171. 171.

    Shen X., Xu Y., Bai Z., Ma D., Niu Q., Meng J., Fan S., Zhang L., Hao Z., Zhang X.J. Transparenchymal renal pelvis injection of recombinant adeno-associated virus serotype 9 vectors is a practical approach for gene delivery in the kidney. Hum. Gene Ther. Methods. 2018;29:251-258.

    Not in our library10.1089/hgtb.2018.148

  172. 172.

    Konkalmatt P., Asico L., Feranil J., Jose P., Armando I. Efficient in vivo gene transfer to murine renal cells using AAV9 vectors (912.7). FASEB J. 2014;28:917.

    Not in our library10.1096/fasebj.28.1_supplement.912.7

  173. 173.

    Schievenbusch S., Strack I., Scheffler M., Nischt R., Coutelle O., Hösel M., Hallek M., Fries J.W.U., Dienes H.-P., Odenthal M., et al. Combined Paracrine and Endocrine AAV9 mediated Expression of Hepatocyte Growth Factor for the Treatment of Renal Fibrosis. Mol. Ther. 2010;18:1302-1309.

    Not in our library10.1038/mt.2010.71

  174. 174.

    Darbey A., Rebourcet D., Curley M., Kilcoyne K., Jeffery N., Reed N., Milne L., Roesl C., Brown P., Smith L.B. A comparison of in vivo viral targeting systems identifies adeno-associated virus serotype 9 (AAV9) as an effective vector for genetic manipulation of Leydig cells in adult mice. Andrology. 2021;9:460-473.

    Not in our library10.1111/andr.12915

  175. 175.

    Limberis M.P., Wilson J.M. Adeno-associated virus serotype 9 vectors transduce murine alveolar and nasal epithelia and can be readministered. Proc. Natl. Acad. Sci. USA. 2006;103:12993-12998.

    Not in our library10.1073/pnas.0601433103

  176. 176.

    Bell C.L., Vandenberghe L.H., Bell P., Limberis M.P., Gao G.-P., Van Vliet K., Agbandje-McKenna M., Wilson J.M. The AAV9 receptor and its modification to improve in vivo lung gene transfer in mice. J. Clin. Investig. 2011;121:2427-2435.

    Not in our library10.1172/jci57367

  177. 177.

    Vance M.A., Mitchell A., Samulski R.J. AAV Biology, Infectivity and Therapeutic Use from Bench to Clinic. Gene Therapy—Principles and Challenges. 2015.

    Not in our library10.5772/61988

  178. 178.

    Vandenberghe L.H., Miller J.R., Gao G.-P., Calcedo R., Wilson J.M. 116. The Proposed AAV Serotypes 10 and 11 Serologically Cross-React with AAV8 and AAV4. Mol. Ther. 2006;13:S47.

    Not in our library10.1016/j.ymthe.2006.08.136

  179. 179.

    Klein R.L., Dayton R.D., Tatom J.B., Henderson K.M., Henning P.P. AAV8, 9, Rh10, Rh43 Vector Gene Transfer in the Rat Brain: Effects of Serotype, Promoter and Purification Method. Mol. Ther. 2008;16:89-96.

    Not in our library10.1038/sj.mt.6300331

  180. 180.

    Mori S., Takeuchi T., Enomoto Y., Kondo K., Sato K., Ono F., Sata T., Kanda T. Tissue distribution of cynomolgus adeno-associated viruses AAV10, AAV11, and AAVcy.7 in naturally infected monkeys. Arch. Virol. 2008;153:375-380.

    Not in our library10.1007/s00705-007-1097-8

  181. 181.

    Polyak S., Mach A., Porvasnik S., Dixon L., Conlon T., Erger K.E., Acosta A., Wright A.J., Campbell-Thompson M., Zolotukhin I., et al. Identification of adeno-associated viral vectors suitable for intestinal gene delivery and modulation of experimental colitis. Am. J. Physiol.-Gastrointest. Liver Physiol. 2012;302:G296-G308.

    Not in our library10.1152/ajpgi.00562.2010

  182. 182.

    Singh M.K., Uehara H., Zhang X., Vashist D., Carroll L., Archer B., Huang Y., Ambati B. Systemic Distribution of AAV10.COMPAng1 in the Ins2Akita mouse. Investig. Ophthalmol. Vis. Sci. 2016;57:5056.

    Not in our library

  183. 183.

    Tian M., Carroll L.S., Tang L., Uehara H., Westenfelder C., Ambati B.K., Huang Y. Systemic AAV10. COMP-Ang1 rescues renal glomeruli and pancreatic islets in type 2 diabetic mice. BMJ Open Diabetes Res. Care. 2020;8:e000882.

    Not in our library10.1136/bmjdrc-2019-000882

  184. 184.

    Han Z., Luo N., Kou J., Li L., Ma W., Peng S., Xu Z., Zhang W., Qiu Y., Wu Y. AAV11 permits efficient retrograde targeting of projection neurons. bioRxiv. 2022.

    Not in our library10.1101/2022.01.13.476170

  185. 185.

    Schmidt M., Voutetakis A., Afione S., Zheng C., Mandikian D., Chiorini J.A. Adeno-Associated Virus Type 12 (AAV12): A Novel AAV Serotype with Sialic Acid- and Heparan Sulfate Proteoglycan-Independent Transduction Activity. J. Virol. 2008;82:1399-1406.

    Not in our library10.1128/jvi.02012-07

  186. 186.

    Schmidt M., Voutetakis A., Afione S., Zheng C., Chiorini J.A. 745. AAV12, Isolated from Vervet Monkey, Has Unique Tropism and Biological as Well as Neutralization Properties. Mol. Ther. 2006;13:S288.

    Not in our library10.1016/j.ymthe.2006.08.827

  187. 187.

    Quinn K., Quirion M.R., Lo C.-Y., Misplon J.A., Epstein S.L., Chiorini J.A. Intranasal Administration of Adeno-associated Virus Type 12 (AAV12) Leads to Transduction of the Nasal Epithelia and Can Initiate Transgene-specific Immune Response. Mol. Ther. 2011;19:1990-1998.

    Not in our library10.1038/mt.2011.146

  188. 188.

    Mietzsch M., Jose A., Chipman P., Bhattacharya N., Daneshparvar N., McKenna R., Agbandje-McKenna M. Completion of the AAV Structural Atlas: Serotype Capsid Structures Reveals Clade-Specific Features. Viruses. 2021;13:101.

    Not in our library10.3390/v13010101

  189. 189.

    Schmidt M., Govindasamy L., Afione S., Kaludov N., Agbandje-McKenna M., Chiorini J.A. Molecular characterization of the heparin-dependent transduction domain on the capsid of a novel adeno-associated virus isolate, AAV(VR-942). J. Virol. 2008;82:8911-8916.

    Not in our library10.1128/jvi.00672-08

  190. 190.

    Huang L.-Y., Halder S., Agbandje-McKenna M. Parvovirus glycan interactions. Curr. Opin. Virol. 2014;7:108-118.

    Not in our library10.1016/j.coviro.2014.05.007

  191. 191.

    Srivastava A.J.C., Insights G.T. Advances and challenges in the use of recombinant AAV vectors for human gene therapy. Cell Gene Ther. Insights. 2016;2:553-575.

    Not in our library10.18609/cgti.2016.061

  192. 192.

    Muzyczka N., Warrington K.H. Custom adeno-associated virus capsids: The next generation of recombinant vectors with novel tropism. Hum. Gene Ther. 2005;16:408-416.

    Not in our library10.1089/hum.2005.16.408

  193. 193.

    Zhang L., Rossi A., Lange L., Meumann N., Koitzsch U., Christie K., Nesbit M.A., Moore C.B.T., Hacker U.T., Morgan M., et al. Capsid Engineering Overcomes Barriers Toward Adeno-Associated Virus Vector-Mediated Transduction of Endothelial Cells. Hum. Gene Ther. 2019;30:1284-1296.

    Not in our library10.1089/hum.2019.027

  194. 194.

    Ward P., Walsh C.E. Chimeric AAV Cap sequences alter gene transduction. Virology. 2009;386:237-248.

    Not in our library10.1016/j.virol.2009.01.012

  195. 195.

    Yang L., Jiang J., Drouin L.M., Agbandje-McKenna M., Chen C., Qiao C., Pu D., Hu X., Wang D.Z., Li J., et al. A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection. Proc. Natl. Acad. Sci. USA. 2009;106:3946-3951.

    Not in our library10.1073/pnas.0813207106

  196. 196.

    White A.F., Mazur M., Sorscher E.J., Zinn K.R., Ponnazhagan S. Genetic modification of adeno-associated viral vector type 2 capsid enhances gene transfer efficiency in polarized human airway epithelial cells. Hum. Gene Ther. 2008;19:1407-1414.

    Not in our library10.1089/hum.2008.117

  197. 197.

    Zhang C., Freistaedter A., Schmelas C., Gunkel M., Dao Thi V.L., Grimm D. An RNA Interference/Adeno-Associated Virus Vector-Based Combinatorial Gene Therapy Approach Against Hepatitis E Virus. Hepatol. Commun. 2022;6:878-888.

    Not in our library10.1002/hep4.1842

  198. 198.

    Van Vliet K.M., Blouin V., Brument N., Agbandje-McKenna M., Snyder R.O. The role of the adeno-associated virus capsid in gene transfer. Methods Mol. Biol. 2008;437:51-91.

    Not in our library10.1007/978-1-59745-210-6_2

  199. 199.

    Perabo L., Endell J., King S., Lux K., Goldnau D., Hallek M., Büning H. Combinatorial engineering of a gene therapy vector: Directed evolution of adeno-associated virus. J. Gene Med. 2006;8:155-162.

    Not in our library10.1002/jgm.849

  200. 200.

    Maheshri N., Koerber J.T., Kaspar B.K., Schaffer D.V. Directed evolution of adeno-associated virus yields enhanced gene delivery vectors. Nat. Biotechnol. 2006;24:198-204.

    Not in our library10.1038/nbt1182

  201. 201.

    Xiao X., deVlaminck W., Monahan J. Adeno-associated virus (AAV) vectors for gene transfer. Adv. Drug Deliv. Rev. 1993;12:201-215.

    Not in our library10.1016/0169-409x(93)90060-h

  202. 202.

    Han Z., Zhong L., Maina N., Hu Z., Li X., Chouthai N.S., Bischof D., Weigel-Van Aken K.A., Slayton W.B., Yoder M.C. Stable integration of recombinant adeno-associated virus vector genomes after transduction of murine hematopoietic stem cells. Hum. Gene Ther. 2008;19:267-278.

    Not in our library10.1089/hum.2007.161

  203. 203.

    Tratschin J.-D., Miller I., Smith M., Carter B.J.M., Biology C. Adeno-associated virus vector for high-frequency integration, expression, and rescue of genes in mammalian cells. Mol. Cell. Biol. 1985;5:3251-3260.

    Not in our library10.1128/mcb.5.11.3251-3260.1985

  204. 204.

    Samulski R., Zhu X., Xiao X., Brook J., Housman D., Epstein N.A., Hunter L. Targeted integration of adeno-associated virus (AAV) into human chromosome 19. EMBO J. 1991;10:3941-3950.

    Not in our library10.1002/j.1460-2075.1991.tb04964.x

  205. 205.

    McCarty D.M., Young S.M., Samulski R.J. Integration of adeno-associated virus (AAV) and recombinant AAV vectors. Annu. Rev. Genet. 2004;38:819-845.

    Not in our library10.1146/annurev.genet.37.110801.143717

  206. 206.

    Walsh C.E., Liu J.M., Xiao X., Young N.S., Nienhuis A.W., Samulski R.J. Regulated high level expression of a human gamma-globin gene introduced into erythroid cells by an adeno-associated virus vector. Proc. Natl. Acad. Sci. USA. 1992;89:7257-7261.

    Not in our library10.1073/pnas.89.15.7257

  207. 207.

    Winocour E., Callaham M., Huberman E. Perturbation of the cell cycle by adeno-associated virus. Virology. 1988;167:393-399.

    Not in our library10.1016/0042-6822(88)90100-6

  208. 208.

    Bantel-Schaal U., Stöhr M.J. Influence of adeno-associated virus on adherence and growth properties of normal cells. J. Virol. 1992;66:773-779.

    Not in our library10.1128/jvi.66.2.773-779.1992

  209. 209.

    Samulski R.J. Adeno-associated virus: Integration at a specific chromosomal locus. Curr. Opin. Genet. Dev. 1993;3:74-80.

    Not in our library10.1016/s0959-437x(05)80344-2

  210. 210.

    Bijlani S., Pang K.M., Sivanandam V., Singh A., Chatterjee S. The Role of Recombinant AAV in Precise Genome Editing. Front. Genome Ed. 2021;3:799722.

    Not in our library10.3389/fgeed.2021.799722

  211. 211.

    Wang D., Tai P.W., Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat. Rev. Drug Discov. 2019;18:358-378.

    Not in our library10.1038/s41573-019-0012-9

  212. 212.
    Humoral Immune Response to AAV · 2013
    No notice
  213. 213.

    Hirsch M.L., Samulski R.J. AAV-mediated gene editing via double-strand break repair. Gene Correction. 2014;291-307.

    Not in our library10.1007/978-1-62703-761-7_19

  214. 214.

    Gray S.J., Nagabhushan Kalburgi S., McCown T.J., Jude Samulski R. Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates. Gene Ther. 2013;20:450-459.

    Not in our library10.1038/gt.2012.101

  215. 215.

    Ge L.-J., Yang F.-H., Li W., Wang T., Lin Y., Feng J., Chen N.-H., Jiang M., Wang J.-H., Hu X.-T. In vivo neuroregeneration to treat ischemic stroke through NeuroD1 AAV-based gene therapy in adult non-human primates. Front. Cell Dev. Biol. 2020;8:590008.

    Not in our library10.3389/fcell.2020.590008

  216. 216.

    Hu C., Lipshutz G.S. AAV-based neonatal gene therapy for hemophilia A: Long-term correction and avoidance of immune responses in mice. Gene Ther. 2012;19:1166-1176.

    Not in our library10.1038/gt.2011.200

  217. 217.
    Cochlear gene therapy with ancestral AAV in adult mice: complete transduction of inner hair cells without cochlear dysfunction · 2017
    Corrected
  218. 218.

    Akil O., Dyka F., Calvet C., Emptoz A., Lahlou G., Nouaille S., Boutet de Monvel J., Hardelin J.-P., Hauswirth W.W., Avan P. Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model. Proc. Natl. Acad. Sci. USA. 2019;116:4496-4501.

    Not in our library10.1073/pnas.1817537116

  219. 219.

    Acland G.M., Aguirre G.D., Ray J., Zhang Q., Aleman T.S., Cideciyan A.V., Pearce-Kelling S.E., Anand V., Zeng Y., Maguire A.M. Gene therapy restores vision in a canine model of childhood blindness. Nat. Genet. 2001;28:92-95.

    Not in our library10.1038/ng0501-92

  220. 220.

    Kodippili K., Hakim C.H., Pan X., Yang H.T., Yue Y., Zhang Y., Shin J.-H., Yang N.N., Duan D. Dual AAV gene therapy for Duchenne muscular dystrophy with a 7-kb mini-dystrophin gene in the canine model. Hum. Gene Ther. 2018;29:299-311.

    Not in our library10.1089/hum.2017.095

  221. 221.

    Gurda B.L., De Guilhem De Lataillade A., Bell P., Zhu Y., Yu H., Wang P., Bagel J., Vite C.H., Sikora T., Hinderer C., et al. Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII. Mol. Ther. J. Am. Soc. Gene Ther. 2016;24:206-216.

    Not in our library10.1038/mt.2015.189

  222. 222.

    Gray-Edwards H.L., Maguire A.S., Salibi N., Ellis L.E., Voss T.L., Diffie E.B., Koehler J., Randle A.N., Taylor A.R., Brunson B.L., et al. 7T MRI predicts amelioration of neurodegeneration in the brain after AAV gene therapy. Mol. Ther.-Methods Clin. Dev. 2020;17:258-270.

    Not in our library10.1016/j.omtm.2019.11.023

  223. 223.

    Choudhury S.R., Fitzpatrick Z., Harris A.F., Maitland S.A., Ferreira J.S., Zhang Y., Ma S., Sharma R.B., Gray-Edwards H.L., Johnson J.A. In vivo selection yields AAV-B1 capsid for central nervous system and muscle gene therapy. Mol. Ther. 2016;24:1247-1257.

    Not in our library10.1038/mt.2016.84

  224. 224.

    McCown T.J. Adeno-associated virus (AAV) vectors in the CNS. Curr. Gene Ther. 2005;5:333-338.

    Not in our library10.2174/1566523054064995

  225. 225.

    Kaplitt M.G., Leone P., Samulski R.J., Xiao X., Pfaff D.W., O’Malley K.L., During M.J. Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Nat. Genet. 1994;8:148-154.

    Not in our library10.1038/ng1094-148

  226. 226.

    McElroy A., Sena-Esteves M., Arjomandnejad M., Keeler A.M., Gray-Edwards H.L. Redosing Adeno-Associated Virus Gene Therapy to the Central Nervous System. Hum. Gene Ther. 2022;33:889-892.

    Not in our library10.1089/hum.2022.170

  227. 227.

    Bartus R.T., Weinberg M.S., Samulski R.J. Parkinson’s Disease Gene Therapy: Success by Design Meets Failure by Efficacy. Mol. Ther. 2014;22:487-497.

    Not in our library10.1038/mt.2013.281

  228. 228.

    Marks W.J., Bartus R.T., Siffert J., Davis C.S., Lozano A., Boulis N., Vitek J., Stacy M., Turner D., Verhagen L., et al. Gene delivery of AAV2-neurturin for Parkinson’s disease: A double-blind, randomised, controlled trial. Lancet Neurol. 2010;9:1164-1172.

    Not in our library10.1016/s1474-4422(10)70254-4

  229. 229.

    Kaplitt M.G., Feigin A., Tang C., Fitzsimons H.L., Mattis P., Lawlor P.A., Bland R.J., Young D., Strybing K., Eidelberg D., et al. Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’s disease: An open label, phase I trial. Lancet. 2007;369:2097-2105.

    Not in our library10.1016/s0140-6736(07)60982-9

  230. 230.

    LeWitt P.A., Rezai A.R., Leehey M.A., Ojemann S.G., Flaherty A.W., Eskandar E.N., Kostyk S.K., Thomas K., Sarkar A., Siddiqui M.S., et al. AAV2-GAD gene therapy for advanced Parkinson’s disease: A double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 2011;10:309-319.

    Not in our library10.1016/s1474-4422(11)70039-4

  231. 231.

    Bartus R.T., Baumann T.L., Siffert J., Herzog C.D., Alterman R., Boulis N., Turner D.A., Stacy M., Lang A.E., Lozano A.M., et al. Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients. Neurology. 2013;80:1698-1701.

    Not in our library10.1212/wnl.0b013e3182904faa

  232. 232.

    Christine C.W., Starr P.A., Larson P.S., Eberling J.L., Jagust W.J., Hawkins R.A., VanBrocklin H.F., Wright J.F., Bankiewicz K.S., Aminoff M.J. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology. 2009;73:1662-1669.

    Not in our library10.1212/wnl.0b013e3181c29356

  233. 233.

    Mittermeyer G., Christine C.W., Rosenbluth K.H., Baker S.L., Starr P., Larson P., Kaplan P.L., Forsayeth J., Aminoff M.J., Bankiewicz K.S. Long-term evaluation of a phase 1 study of AADC gene therapy for Parkinson’s disease. Hum. Gene Ther. 2012;23:377-381.

    Not in our library10.1089/hum.2011.220

  234. 234.

    Chien Y.H., Lee N.C., Tseng S.H., Tai C.H., Muramatsu S.I., Byrne B.J., Hwu W.L. Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: An open-label, phase 1/2 trial. Lancet Child Adolesc. Health. 2017;1:265-273.

    Not in our library10.1016/s2352-4642(17)30125-6

  235. 235.

    Kolb S.J., Kissel J.T. Spinal muscular atrophy: A timely review. Arch. Neurol. 2011;68:979-984.

    Not in our library10.1001/archneurol.2011.74

  236. 236.

    Aguti S., Malerba A., Zhou H. The progress of AAV-mediated gene therapy in neuromuscular disorders. Expert Opin. Biol. Ther. 2018;18:681-693.

    Not in our library10.1080/14712598.2018.1479739

  237. 237.

    Spahiu L., Behluli E., Peterlin B., Nefic H., Hadziselimovic R., Liehr T., Temaj G. Mucopolysaccharidosis III: Molecular basis and treatment. Pediatr. Endocrinol. Diabetes Metab. 2021;27:201-208.

    Not in our library10.5114/pedm.2021.109270

  238. 238.

    Watson G.L., Sayles J.N., Chen C., Elliger S.S., Elliger C.A., Raju N.R., Kurtzman G.J., Podsakoff G.M. Treatment of lysosomal storage disease in MPS VII mice using a recombinant adeno-associated virus. Gene Ther. 1998;5:1642-1649.

    Not in our library10.1038/sj.gt.3300775

  239. 239.

    Skorupa A.F., Fisher K.J., Wilson J.M., Parente M.K., Wolfe J.H. Sustained production of beta-glucuronidase from localized sites after AAV vector gene transfer results in widespread distribution of enzyme and reversal of lysosomal storage lesions in a large volume of brain in mucopolysaccharidosis VII mice. Exp. Neurol. 1999;160:17-27.

    Not in our library10.1006/exnr.1999.7176

  240. 240.

    Daly T.M., Vogler C., Levy B., Haskins M.E., Sands M.S. Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease. Proc. Natl. Acad. Sci. USA. 1999;96:2296-2300.

    Not in our library10.1073/pnas.96.5.2296

  241. 241.

    Marcó S., Haurigot V., Jaén M.L., Ribera A., Sánchez V., Molas M., Garcia M., León X., Roca C., Sánchez X., et al. Seven-year follow-up of durability and safety of AAV CNS gene therapy for a lysosomal storage disorder in a large animal. Mol. Ther.-Methods Clin. Dev. 2021;23:370-389.

    Not in our library10.1016/j.omtm.2021.09.017

  242. 242.

    Shaimardanova A.A., Chulpanova D.S., Solovyeva V.V., Mullagulova A.I., Kitaeva K.V., Allegrucci C., Rizvanov A.A. Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches. Front. Med. 2020;7:576221.

    Not in our library10.3389/fmed.2020.576221

  243. 243.

    Piguet F., Sondhi D., Piraud M., Fouquet F., Hackett N.R., Ahouansou O., Vanier M.-T., Bieche I., Aubourg P., Crystal R.G. Correction of brain oligodendrocytes by AAVrh. 10 intracerebral gene therapy in metachromatic leukodystrophy mice. Hum. Gene Ther. 2012;23:903-914.

    Not in our library10.1089/hum.2012.015

  244. 244.

    Kurai T., Hisayasu S., Kitagawa R., Migita M., Suzuki H., Hirai Y., Shimada T. AAV1 mediated co-expression of formylglycine-generating enzyme and arylsulfatase a efficiently corrects sulfatide storage in a mouse model of metachromatic leukodystrophy. Mol. Ther. 2007;15:38-43.

    Not in our library10.1038/sj.mt.6300012

  245. 245.

    Miyake N., Miyake K., Asakawa N., Yamamoto M., Shimada T. Long-term correction of biochemical and neurological abnormalities in MLD mice model by neonatal systemic injection of an AAV serotype 9 vector. Gene Ther. 2014;21:427-433.

    Not in our library10.1038/gt.2014.17

  246. 246.

    Sevin C., Benraiss A., Van Dam D., Bonnin D., Nagels G., Verot L., Laurendeau I., Vidaud M., Gieselmann V., Vanier M. Intracerebral adeno-associated virus-mediated gene transfer in rapidly progressive forms of metachromatic leukodystrophy. Hum. Mol. Genet. 2006;15:53-64.

    Not in our library10.1093/hmg/ddi425

  247. 247.

    Shaimardanova A.A., Chulpanova D.S., Solovyeva V.V., Aimaletdinov A.M., Rizvanov A.A. Functionality of a bicistronic construction containing HEXA and HEXB genes encoding β-hexosaminidase A for cell-mediated therapy of GM2 gangliosidoses. Neural Regen. Res. 2022;17:122-129.

    Not in our library10.4103/1673-5374.314310

  248. 248.

    Taghian T., Marosfoi M.G., Puri A.S., Cataltepe O.I., King R.M., Diffie E.B., Maguire A.S., Martin D.R., Fernau D., Batista A.R., et al. A Safe and Reliable Technique for CNS Delivery of AAV Vectors in the Cisterna Magna. Mol. Ther. J. Am. Soc. Gene Ther. 2020;28:411-421.

    Not in our library10.1016/j.ymthe.2019.11.012

  249. 249.
    New Approaches to Tay-Sachs Disease Therapy · 2018
    Not checked
  250. 250.

    Cachón-González M.B., Wang S.Z., Lynch A., Ziegler R., Cheng S.H., Cox T.M. Effective gene therapy in an authentic model of Tay-Sachs-related diseases. Proc. Natl. Acad. Sci. USA. 2006;103:10373-10378.

    Not in our library10.1073/pnas.0603765103

  251. 251.

    Gray-Edwards H.L., Randle A.N., Maitland S.A., Benatti H.R., Hubbard S.M., Canning P.F., Vogel M.B., Brunson B.L., Hwang M., Ellis L.E., et al. Adeno-Associated Virus Gene Therapy in a Sheep Model of Tay-Sachs Disease. Hum. Gene Ther. 2018;29:312-326.

    Not in our library10.1089/hum.2017.163

  252. 252.

    Rockwell H.E., McCurdy V.J., Eaton S.C., Wilson D.U., Johnson A.K., Randle A.N., Bradbury A.M., Gray-Edwards H.L., Baker H.J., Hudson J.A., et al. AAV-mediated gene delivery in a feline model of Sandhoff disease corrects lysosomal storage in the central nervous system. ASN Neuro. 2015;7:1759091415569908.

    Not in our library10.1177/1759091415569908

  253. 253.

    Sevin C., Roujeau T., Cartier N., Baugnon T., Adamsbaum C., Piraud M., Martino S., Mouiller P., Couzinié C., Bellesme C. Intracerebral Gene Therapy in Children with Metachromatic Leukodystrophy: Results of a Phase I/II Trial. Mol. Genet. Metab. 2018;123:S129.

    Not in our library10.1016/j.ymgme.2017.12.352

  254. 254.

    Tenenbaum L., Chtarto A., Lehtonen E., Velu T., Brotchi J., Levivier M. Recombinant AAV-mediated gene delivery to the central nervous system. J. Gene Med. 2004;6:S212-S222.

    Not in our library10.1002/jgm.506

  255. 255.

    Surendran S., Michals-Matalon K., Quast M.J., Tyring S.K., Wei J., Ezell E.L., Matalon R. Canavan disease: A monogenic trait with complex genomic interaction. Mol. Genet. Metab. 2003;80:74-80.

    Not in our library10.1016/j.ymgme.2003.08.015

  256. 256.

    Matalon R., Surendran S., Rady P.L., Quast M.J., Campbell G.A., Matalon K.M., Tyring S.K., Wei J., Peden C.S., Ezell E.L., et al. Adeno-associated virus-mediated aspartoacylase gene transfer to the brain of knockout mouse for canavan disease. Mol. Ther. J. Am. Soc. Gene Ther. 2003;7:580-587.

    Not in our library10.1016/s1525-0016(03)00066-2

  257. 257.

    Janson C., McPhee S., Bilaniuk L., Haselgrove J., Testaiuti M., Freese A., Wang D.J., Shera D., Hurh P., Rupin J., et al. Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. Hum. Gene Ther. 2002;13:1391-1412.

    Not in our library10.1089/104303402760128612

  258. 258.

    rAAV-Olig001-ASPA Gene Therapy for Treatment of Children With Typical Canavan Disease.

    Not in our library

  259. 259.

    Canavan-Single Patient IND.

    Not in our library

  260. 260.

    A Study of AAV9 Gene Therapy in Participants With Canavan Disease.

    Not in our library

  261. 261.
    Krabbe Disease: Prospects of Finding a Cure Using AAV Gene Therapy · 2021
    Not checked
  262. 262.

    Rafi M.A., Rao H.Z., Passini M.A., Curtis M., Vanier M.T., Zaka M., Luzi P., Wolfe J.H., Wenger D.A. AAV-mediated expression of galactocerebrosidase in brain results in attenuated symptoms and extended life span in murine models of globoid cell leukodystrophy. Mol. Ther. 2005;11:734-744.

    Not in our library10.1016/j.ymthe.2004.12.020

  263. 263.

    Lin D.-S., Hsiao C.-D., Liau I., Lin S.-P., Chiang M.-F., Chuang C.-K., Wang T.-J., Wu T.-Y., Jian Y.-R., Huang S.-F., et al. CNS-targeted AAV5 gene transfer results in global dispersal of vector and prevention of morphological and function deterioration in CNS of globoid cell leukodystrophy mouse model. Mol. Genet. Metab. 2011;103:367-377.

    Not in our library10.1016/j.ymgme.2011.05.005

  264. 264.

    Lin D., Fantz C.R., Levy B., Rafi M.A., Vogler C., Wenger D.A., Sands M.S. AAV2/5 vector expressing galactocerebrosidase ameliorates CNS disease in the murine model of globoid-cell leukodystrophy more efficiently than AAV2. Mol. Ther. 2005;12:422-430.

    Not in our library10.1016/j.ymthe.2005.04.019

  265. 265.

    Karumuthil-Melethil S., Marshall M.S., Heindel C., Jakubauskas B., Bongarzone E.R., Gray S.J. Intrathecal administration of AAV/GALC vectors in 10–11-day-old twitcher mice improves survival and is enhanced by bone marrow transplant. J. Neurosci. Res. 2016;94:1138-1151.

    Not in our library10.1002/jnr.23882

  266. 266.

    Bradbury A.M., Rafi M.A., Bagel J.H., Brisson B.K., Marshall M.S., Pesayco Salvador J., Jiang X., Swain G.P., Prociuk M.L., ODonnell P.A. AAVrh10 gene therapy ameliorates central and peripheral nervous system disease in canine globoid cell leukodystrophy (Krabbe disease). Hum. Gene Ther. 2018;29:785-801.

    Not in our library10.1089/hum.2017.151

  267. 267.

    Bradbury A.M., Bagel J.H., Nguyen D., Lykken E.A., Salvador J.P., Jiang X., Swain G.P., Assenmacher C.A., Hendricks I.J., Miyadera K. Krabbe disease successfully treated via monotherapy of intrathecal gene therapy. J. Clin. Investig. 2020;130:4906-4920.

    Not in our library10.1172/jci133953

  268. 268.

    Hori T., Fukutome M., Maejima C., Matsushima H., Kobayashi K., Kitazawa S., Kitahara R., Kitano K., Kobayashi K., Moritoh S., et al. Gene delivery to cone photoreceptors by subretinal injection of rAAV2/6 in the mouse retina. Biochem. Biophys. Res. Commun. 2019;515:222-227.

    Not in our library10.1016/j.bbrc.2019.05.117

  269. 269.

    Le Meur G., Lebranchu P., Billaud F., Adjali O., Schmitt S., Bézieau S., Péréon Y., Valabregue R., Ivan C., Darmon C., et al. Safety and Long-Term Efficacy of AAV4 Gene Therapy in Patients with RPE65 Leber Congenital Amaurosis. Mol. Ther. J. Am. Soc. Gene Ther. 2018;26:256-268.

    Not in our library10.1016/j.ymthe.2017.09.014

  270. 270.

    Le Meur G., Lebranchu P., Pereon Y., Billaud F., Ivan C., Chauveau C., Rolling F., Weber M. Efficacy and safety of gene therapy with AAV4 in childhood blindness due to rpe65 mutations. Acta Ophthalmol. 2012;90.

    Not in our library10.1111/j.1755-3768.2012.4223.x

  271. 271.

    Trapani I., Auricchio A. Seeing the Light after 25 Years of Retinal Gene Therapy. Trends Mol. Med. 2018;24:669-681.

    Not in our library10.1016/j.molmed.2018.06.006

  272. 272.

    MacLaren R.E., Groppe M., Barnard A.R., Cottriall C.L., Tolmachova T., Seymour L., Clark K.R., During M.J., Cremers F.P.M., Black G.C.M., et al. Retinal gene therapy in patients with choroideremia: Initial findings from a phase 1/2 clinical trial. Lancet. 2014;383:1129-1137.

    Not in our library10.1016/s0140-6736(13)62117-0

  273. 273.

    Faynus M.A., Clegg D.O., Birbrair A. Chapter 7—Modeling inherited retinal dystrophies using induced pluripotent stem cells. Current Progress in iPSC Disease Modeling. 2022;157-184.

    Not in our library10.1016/b978-0-323-85765-9.00005-9

  274. 274.

    Russell S., Bennett J., Wellman J.A., Chung D.C., Yu Z.-F., Tillman A., Wittes J., Pappas J., Elci O., McCague S., et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: A randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390:849-860.

    Not in our library10.1016/s0140-6736(17)31868-8

  275. 275.

    Bouquet C., Vignal Clermont C., Galy A., Fitoussi S., Blouin L., Munk M.R., Valero S., Meunier S., Katz B., Sahel J.A., et al. Immune Response and Intraocular Inflammation in Patients With Leber Hereditary Optic Neuropathy Treated With Intravitreal Injection of Recombinant Adeno-Associated Virus 2 Carrying the ND4 Gene: A Secondary Analysis of a Phase 1/2 Clinical Trial. JAMA Ophthalmol. 2019;137:399-406.

    Not in our library10.1001/jamaophthalmol.2018.6902

  276. 276.

    Feuer W.J., Schiffman J.C., Davis J.L., Porciatti V., Gonzalez P., Koilkonda R.D., Yuan H., Lalwani A., Lam B.L., Guy J. Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results. Ophthalmology. 2016;123:558-570.

    Not in our library10.1016/j.ophtha.2015.10.025

  277. 277.

    Cehajic-Kapetanovic J., Xue K., Martinez-Fernandez de la Camara C., Nanda A., Davies A., Wood L.J., Salvetti A.P., Fischer M.D., Aylward J.W., Barnard A.R., et al. Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR. Nat. Med. 2020;26:354-359.

    Not in our library10.1038/s41591-020-0763-1

  278. 278.

    Cukras C., Wiley H.E., Jeffrey B.G., Sen H.N., Turriff A., Zeng Y., Vijayasarathy C., Marangoni D., Ziccardi L., Kjellstrom S., et al. Retinal AAV8-RS1 Gene Therapy for X-Linked Retinoschisis: Initial Findings from a Phase I/IIa Trial by Intravitreal Delivery. Mol. Ther. 2018;26:2282-2294.

    Not in our library10.1016/j.ymthe.2018.05.025

  279. 279.

    Mishra A., Vijayasarathy C., Cukras C.A., Wiley H.E., Sen H.N., Zeng Y., Wei L.L., Sieving P.A. Immune function in X-linked retinoschisis subjects in an AAV8-RS1 phase I/IIa gene therapy trial. Mol. Ther. 2021;29:2030-2040.

    Not in our library10.1016/j.ymthe.2021.02.013

  280. 280.
    Safety and Vision Outcomes of Subretinal Gene Therapy Targeting Cone Photoreceptors in Achromatopsia · 2020
    No notice
  281. 281.

    Kahle N.A., Peters T., Zobor D., Kuehlewein L., Kohl S., Zhour A., Werner A., Seitz I.P., Sothilingam V., Michalakis S., et al. Development of Methodology and Study Protocol: Safety and Efficacy of a Single Subretinal Injection of rAAV.hCNGA3 in Patients with CNGA3-Linked Achromatopsia Investigated in an Exploratory Dose-Escalation Trial. Hum. Gene Ther. Clin. Dev. 2018;29:121-131.

    Not in our library10.1089/humc.2018.088

  282. 282.

    Lalwani A.K., Walsh B.J., Reilly P.G., Muzyczka N., Mhatre A.N. Development of in vivo gene therapy for hearing disorders: Introduction of adeno-associated virus into the cochlea of the guinea pig. Gene Ther. 1996;3:588-592.

    Not in our library

  283. 283.

    Sondhi D., Stiles K.M., De B.P., Crystal R.G. Genetic Modification of the Lung Directed Toward Treatment of Human Disease. Hum. Gene Ther. 2017;28:3-84.

    Not in our library10.1089/hum.2016.152

  284. 284.

    McLachlan G., Alton E., Boyd A.C., Clarke N.K., Davies J.C., Gill D.R., Griesenbach U., Hickmott J.W., Hyde S.C., Miah K.M., et al. Progress in Respiratory Gene Therapy. Hum. Gene Ther. 2022;33:893-912.

    Not in our library10.1089/hum.2022.172

  285. 285.

    Burney T.J., Davies J.C. Gene therapy for the treatment of cystic fibrosis. Appl. Clin. Genet. 2012;5:29.

    Not in our library10.2147/tacg.s8873

  286. 286.

    Flotte T.R., Afione S.A., Conrad C., McGrath S.A., Solow R., Oka H., Zeitlin P.L., Guggino W.B., Carter B.J. Stable in vivo expression of the cystic fibrosis transmembrane conductance regulator with an adeno-associated virus vector. Proc. Natl. Acad. Sci. USA. 1993;90:10613-10617.

    Not in our library10.1073/pnas.90.22.10613

  287. 287.

    Guggino W.B., Cebotaru L. Gene therapy for cystic fibrosis paved the way for the use of adeno-associated virus in gene therapy. Hum. Gene Ther. 2020;31:538-541.

    Not in our library10.1089/hum.2020.046

  288. 288.

    Wagner J.A., Reynolds T., Moran M.L., Moss R.B., Wine J.J., Flotte T.R., Gardner P. Efficient and persistent gene transfer of AAV-CFTR in maxillary sinus. Lancet. 1998;351:1702-1703.

    Not in our library10.1016/s0140-6736(05)77740-0

  289. 289.

    Wagner J.A., Nepomuceno I.B., Messner A.H., Moran M.L., Batson E.P., Dimiceli S., Brown B.W., Desch J.K., Norbash A.M., Conrad C.K. A phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies. Hum. Gene Ther. 2002;13:1349-1359.

    Not in our library10.1089/104303402760128577

  290. 290.

    Aitken M., Moss R., Waltz D., Dovey M., Tonelli M., McNamara S., Gibson R., Ramsey B., Carter B., Reynolds T. A phase I study of aerosolized administration of tgAAVCF to cystic fibrosis subjects with mild lung disease. Hum. Gene Ther. 2001;12:1907-1916.

    Not in our library10.1089/104303401753153956

  291. 291.

    Flotte T.R., Zeitlin P.L., Reynolds T.C., Heald A.E., Pedersen P., Beck S., Conrad C.K., Brass-Ernst L., Humphries M., Sullivan K. Phase I trial of intranasal and endobronchial administration of a recombinant adeno-associated virus serotype 2 (rAAV2)-CFTR vector in adult cystic fibrosis patients: A two-part clinical study. Hum. Gene Ther. 2003;14:1079-1088.

    Not in our library10.1089/104303403322124792

  292. 292.

    Moss R.B., Rodman D., Spencer L.T., Aitken M.L., Zeitlin P.L., Waltz D., Milla C., Brody A.S., Clancy J.P., Ramsey B. Repeated adeno-associated virus serotype 2 aerosol-mediated cystic fibrosis transmembrane regulator gene transfer to the lungs of patients with cystic fibrosis: A multicenter, double-blind, placebo-controlled trial. Chest. 2004;125:509-521.

    Not in our library10.1378/chest.125.2.509

  293. 293.

    Moss R.B., Milla C., Colombo J., Accurso F., Zeitlin P.L., Clancy J.P., Spencer L.T., Pilewski J., Waltz D.A., Dorkin H.L. Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: A randomized placebo-controlled phase 2B trial. Hum. Gene Ther. 2007;18:726-732.

    Not in our library10.1089/hum.2007.022

  294. 294.

    Kurosaki F., Uchibori R., Mato N., Sehara Y., Saga Y., Urabe M., Mizukami H., Sugiyama Y., Kume A. Optimization of adeno-associated virus vector-mediated gene transfer to the respiratory tract. Gene Ther. 2017;24:290-297.

    Not in our library10.1038/gt.2017.19

  295. 295.

    Cooney A.L., McCray P.B., Sinn P.L. Cystic Fibrosis Gene Therapy: Looking Back, Looking Forward. Genes. 2018;9:538.

    Not in our library10.3390/genes9110538

  296. 296.

    Stiles K.M., Sondhi D., Kaminsky S.M., De B.P., Rosenberg J.B., Crystal R.G. Intrapleural Gene Therapy for Alpha-1 Antitrypsin Deficiency-Related Lung Disease. Chronic Obstr. Pulm. Dis. 2018;5:244-257.

    Not in our library10.15326/jcopdf.5.4.2017.0160

  297. 297.

    Song S., Embury J., Laipis P., Berns K., Crawford J., Flotte T. Stable therapeutic serum levels of human alpha-1 antitrypsin (AAT) after portal vein injection of recombinant adeno-associated virus (rAAV) vectors. Gene Ther. 2001;8:1299-1306.

    Not in our library10.1038/sj.gt.3301422

  298. 298.

    Conlon T.J., Cossette T., Erger K., Choi Y.-K., Clarke T., Scott-Jorgensen M., Song S., Campbell-Thompson M., Crawford J., Flotte T.R. Efficient Hepatic Delivery and Expression from a Recombinant Adeno-associated Virus 8 Pseudotyped α1-Antitrypsin Vector. Mol. Ther. 2005;12:867-875.

    Not in our library10.1016/j.ymthe.2005.05.016

  299. 299.

    De B., Heguy A., Leopold P.L., Wasif N., Korst R.J., Hackett N.R., Crystal R.G. Intrapleural administration of a serotype 5 adeno-associated virus coding for α1-antitrypsin mediates persistent, high lung and serum levels of α1-antitrypsin. Mol. Ther. 2004;10:1003-1010.

    Not in our library10.1016/j.ymthe.2004.08.022

  300. 300.

    Chulay J.D., Ye G.J., Thomas D.L., Knop D.R., Benson J.M., Hutt J.A., Wang G., Humphries M., Flotte T.R. Preclinical evaluation of a recombinant adeno-associated virus vector expressing human alpha-1 antitrypsin made using a recombinant herpes simplex virus production method. Hum. Gene Ther. 2011;22:155-165.

    Not in our library10.1089/hum.2010.118

  301. 301.

    Limberis M.P., Vandenberghe L.H., Zhang L., Pickles R.J., Wilson J.M. Transduction Efficiencies of Novel AAV Vectors in Mouse Airway Epithelium In Vivo and Human Ciliated Airway Epithelium In Vitro. Mol. Ther. 2009;17:294-301.

    Not in our library10.1038/mt.2008.261

  302. 302.

    Liqun Wang R., McLaughlin T., Cossette T., Tang Q., Foust K., Campbell-Thompson M., Martino A., Cruz P., Loiler S., Mueller C., et al. Recombinant AAV Serotype and Capsid Mutant Comparison for Pulmonary Gene Transfer of α-1-Antitrypsin Using Invasive and Noninvasive Delivery. Mol. Ther. 2009;17:81-87.

    Not in our library10.1038/mt.2008.217

  303. 303.

    Chiuchiolo M.J., Kaminsky S.M., Sondhi D., Hackett N.R., Rosenberg J.B., Frenk E.Z., Hwang Y., Van de Graaf B.G., Hutt J.A., Wang G., et al. Intrapleural administration of an AAVrh.10 vector coding for human α1-antitrypsin for the treatment of α1-antitrypsin deficiency. Hum. Gene Ther. Clin. Dev. 2013;24:161-173.

    Not in our library10.1089/humc.2013.168

  304. 304.

    De B.P., Heguy A., Hackett N.R., Ferris B., Leopold P.L., Lee J., Pierre L., Gao G., Wilson J.M., Crystal R.G. High Levels of Persistent Expression of α1-Antitrypsin Mediated by the Nonhuman Primate Serotype rh.10 Adeno-associated Virus Despite Preexisting Immunity to Common Human Adeno-associated Viruses. Mol. Ther. 2006;13:67-76.

    Not in our library10.1016/j.ymthe.2005.09.003

  305. 305.

    Flotte T.R., Conlon T.J., Poirier A., Campbell-Thompson M., Byrne B.J. Preclinical characterization of a recombinant adeno-associated virus type 1-pseudotyped vector demonstrates dose-dependent injection site inflammation and dissemination of vector genomes to distant sites. Hum. Gene Ther. 2007;18:245-256.

    Not in our library10.1089/hum.2006.113

  306. 306.

    Zavorotinskaya T., Tomkinson A., Murphy J.E. Treatment of experimental asthma by long-term gene therapy directed against IL-4 and IL-13. Mol. Ther. 2003;7:155-162.

    Not in our library10.1016/s1525-0016(02)00050-3

  307. 307.

    Kang M.H., van Lieshout L.P., Xu L., Domm J.M., Vadivel A., Renesme L., Mühlfeld C., Hurskainen M., Mižíková I., Pei Y. A lung tropic AAV vector improves survival in a mouse model of surfactant B deficiency. Nat. Commun. 2020;11:3929.

    Not in our library10.1038/s41467-020-17577-8

  308. 308.

    Cooney A.L., Wambach J.A., Sinn P.L., McCray P.B. Gene therapy potential for genetic disorders of surfactant dysfunction. Front. Genome Ed. 2021;3:43.

    Not in our library10.3389/fgeed.2021.785829

  309. 309.

    Guse K., Suzuki M., Sule G., Bertin T.K., Tyynismaa H., Ahola-Erkkilä S., Palmer D., Suomalainen A., Ng P., Cerullo V., et al. Capsid-modified adenoviral vectors for improved muscle-directed gene therapy. Hum. Gene Ther. 2012;23:1065-1070.

    Not in our library10.1089/hum.2012.003

  310. 310.

    Tang Y., Cummins J., Huard J., Wang B. AAV-directed muscular dystrophy gene therapy. Expert Opin. Biol. Ther. 2010;10:395-408.

    Not in our library10.1517/14712591003604690

  311. 311.

    Kota J., Handy C.R., Haidet A.M., Montgomery C.L., Eagle A., Rodino-Klapac L.R., Tucker D., Shilling C.J., Therlfall W.R., Walker C.M., et al. Follistatin gene delivery enhances muscle growth and strength in nonhuman primates. Sci. Transl. Med. 2009;1:6ra15.

    Not in our library10.1126/scitranslmed.3000112

  312. 312.

    Gregorevic P., Allen J.M., Minami E., Blankinship M.J., Haraguchi M., Meuse L., Finn E., Adams M.E., Froehner S.C., Murry C.E., et al. rAAV6-microdystrophin preserves muscle function and extends lifespan in severely dystrophic mice. Nat. Med. 2006;12:787-789.

    Not in our library10.1038/nm1439

  313. 313.

    Wang B., Li J., Fu F.H., Xiao X. Systemic human minidystrophin gene transfer improves functions and life span of dystrophin and dystrophin/utrophin-deficient mice. J. Orthop. Res. Off. Publ. Orthop. Res. Soc. 2009;27:421-426.

    Not in our library10.1002/jor.20781

  314. 314.

    Zhu T., Zhou L., Mori S., Wang Z., McTiernan C.F., Qiao C., Chen C., Wang D.W., Li J., Xiao X. Sustained Whole-Body Functional Rescue in Congestive Heart Failure and Muscular Dystrophy Hamsters by Systemic Gene Transfer. Circulation. 2005;112:2650-2659.

    Not in our library10.1161/circulationaha.105.565598

  315. 315.

    Pacak C.A., Walter G.A., Gaidosh G., Bryant N., Lewis M.A., Germain S., Mah C.S., Campbell K.P., Byrne B.J. Long-term skeletal muscle protection after gene transfer in a mouse model of LGMD-2D. Mol. Ther. J. Am. Soc. Gene Ther. 2007;15:1775-1781.

    Not in our library10.1038/sj.mt.6300246

  316. 316.

    Fougerousse F., Bartoli M., Poupiot J., Arandel L., Durand M., Guerchet N., Gicquel E., Danos O., Richard I. Phenotypic Correction of α-Sarcoglycan Deficiency by Intra-arterial Injection of a Muscle-specific Serotype 1 rAAV Vector. Mol. Ther. J. Am. Soc. Gene Ther. 2007;15:53-61.

    Not in our library10.1038/sj.mt.6300022

  317. 317.

    Cordier L., Hack A.A., Scott M.O., Barton-Davis E.R., Gao G., Wilson J.M., McNally E.M., Sweeney H.L. Rescue of skeletal muscles of gamma-sarcoglycan-deficient mice with adeno-associated virus-mediated gene transfer. Mol. Ther. J. Am. Soc. Gene Ther. 2000;1:119-129.

    Not in our library10.1006/mthe.1999.0019

  318. 318.

    Bartoli M., Roudaut C., Martin S., Fougerousse F., Suel L., Poupiot J., Gicquel E., Noulet F., Danos O., Richard I. Safety and efficacy of AAV-mediated calpain 3 gene transfer in a mouse model of limb-girdle muscular dystrophy type 2A. Mol. Ther. J. Am. Soc. Gene Ther. 2006;13:250-259.

    Not in our library10.1016/j.ymthe.2005.09.017

  319. 319.

    Duan D. Systemic AAV Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy. Mol. Ther. 2018;26:2337-2356.

    Not in our library10.1016/j.ymthe.2018.07.011

  320. 320.

    Bowles D.E., McPhee S.W.J., Li C., Gray S.J., Samulski J.J., Camp A.S., Li J., Wang B., Monahan P.E., Rabinowitz J.E., et al. Phase 1 Gene Therapy for Duchenne Muscular Dystrophy Using a Translational Optimized AAV Vector. Mol. Ther. 2012;20:443-455.

    Not in our library10.1038/mt.2011.237

  321. 321.

    World Health Organization. Cardiovascular Diseases (CVDs).

    Not in our library

  322. 322.

    Jiang H., Lillicrap D., Patarroyo-White S., Liu T., Qian X., Scallan C.D., Powell S., Keller T., McMurray M., Labelle A., et al. Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs. Blood. 2006;108:107-115.

    Not in our library10.1182/blood-2005-12-5115

  323. 323.

    Zsebo K., Yaroshinsky A., Rudy J.J., Wagner K., Greenberg B., Jessup M., Hajjar R.J. Long-Term Effects of AAV1/SERCA2a Gene Transfer in Patients With Severe Heart Failure. Circ. Res. 2014;114:101-108.

    Not in our library10.1161/circresaha.113.302421

  324. 324.

    Nguyen T.H., Ferry N. Liver gene therapy: Advances and hurdles. Gene Ther. 2004;11:S76-S84.

    Not in our library10.1038/sj.gt.3302373

  325. 325.

    Członkowska A., Litwin T., Dusek P., Ferenci P., Lutsenko S., Medici V., Rybakowski J.K., Weiss K.H., Schilsky M.L. Wilson disease. Nat. Rev. Dis. Prim. 2018;4:21.

    Not in our library10.1038/s41572-018-0018-3

  326. 326.

    Murillo O., Collantes M., Gazquez C., Moreno D., Hernandez-Alcoceba R., Barberia M., Ecay M., Tamarit B., Douar A., Ferrer V., et al. High value of (64)Cu as a tool to evaluate the restoration of physiological copper excretion after gene therapy in Wilson’s disease. Mol. Ther. Methods Clin. Dev. 2022;26:98-106.

    Not in our library10.1016/j.omtm.2022.06.001

  327. 327.

    Murillo O., Moreno D., Gazquez C., Barberia M., Cenzano I., Navarro I., Uriarte I., Sebastian V., Arruebo M., Ferrer V., et al. Liver Expression of a MiniATP7B Gene Results in Long-Term Restoration of Copper Homeostasis in a Wilson Disease Model in Mice. Hepatology. 2019;70:108-126.

    Not in our library10.1002/hep.30535

  328. 328.

    Crigler J.F., Najjar V.A. Congenital familial nonhemolytic jaundice with kernicterus. Pediatrics. 1952;10:169-180.

    Not in our library

  329. 329.

    Gene Therapy for Severe Crigler Najjar Syndrome.

    Not in our library

  330. 330.

    Shi X., Aronson S.J., Ten Bloemendaal L., Duijst S., Bakker R.S., de Waart D.R., Bortolussi G., Collaud F., Oude Elferink R.P., Muro A.F., et al. Efficacy of AAV8-hUGT1A1 with Rapamycin in neonatal, suckling, and juvenile rats to model treatment in pediatric CNs patients. Mol. Ther. Methods Clin. Dev. 2021;20:287-297.

    Not in our library10.1016/j.omtm.2020.11.016

  331. 331.

    Golden S.H., Robinson K.A., Saldanha I., Anton B., Ladenson P.W. Clinical review: Prevalence and incidence of endocrine and metabolic disorders in the United States: A comprehensive review. J. Clin. Endocrinol. Metab. 2009;94:1853-1878.

    Not in our library10.1210/jc.2008-2291

  332. 332.

    Wilson J.D. Prospects for research for disorders of the endocrine system. JAMA. 2001;285:624-627.

    Not in our library10.1001/jama.285.5.624

  333. 333.

    Barzon L., Bonaguro R., Palù G., Boscaro M. New perspectives for gene therapy in endocrinology. Eur. J. Endocrinol. 2000;143:447-466.

    Not in our library10.1530/eje.0.1430447

  334. 334.

    Chellappan D.K., Sivam N.S., Teoh K.X., Leong W.P., Fui T.Z., Chooi K., Khoo N., Yi F.J., Chellian J., Cheng L.L., et al. Gene therapy and type 1 diabetes mellitus. Biomed. Pharmacother. 2018;108:1188-1200.

    Not in our library10.1016/j.biopha.2018.09.138

  335. 335.

    Atkinson M.A., Melmed S., Polonsky K.S., Larsen P.R., Kronenberg H.M. Chapter 32—Type 1 Diabetes Mellitus. Williams Textbook of Endocrinology. 2016;1451-1483.

    Not in our library10.1016/b978-0-323-29738-7.00032-0

  336. 336.

    Flores R.R., Zhou L., Robbins P.D. Expression of IL-2 in β cells by AAV8 gene transfer in pre-diabetic NOD mice prevents diabetes through activation of FoxP3-positive regulatory T cells. Gene Ther. 2014;21:715-722.

    Not in our library10.1038/gt.2014.45

  337. 337.

    Zhang Y.C., Pileggi A., Agarwal A., Molano R.D., Powers M., Brusko T., Wasserfall C., Goudy K., Zahr E., Poggioli R., et al. Adeno-Associated Virus-Mediated IL-10 Gene Therapy Inhibits Diabetes Recurrence in Syngeneic Islet Cell Transplantation of NOD Mice. Diabetes. 2003;52:708-716.

    Not in our library10.2337/diabetes.52.3.708

  338. 338.

    El Khatib M., Sakuma T., Tonne J.M., Mohamed M.S., Holditch S.J., Lu B., Kudva Y.C., Ikeda Y. β-Cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection. Gene Ther. 2015;22:430-438.

    Not in our library10.1038/gt.2015.18

  339. 339.

    RGX-314 Gene Therapy Administered in the Suprachoroidal Space for Participants With Diabetic Retinopathy (DR) without Center Involved-Diabetic Macular Edema (CI-DME).

    Not in our library

  340. 340.

    Borden K.L. Pondering the promyelocytic leukemia protein (PML) puzzle: Possible functions for PML nuclear bodies. Mol. Cell. Biol. 2002;22:5259-5269.

    Not in our library10.1128/mcb.22.15.5259-5269.2002

  341. 341.

    Almaghrabi S., Azzouz M., Tazi Ahnini R. AAV9-mediated AIRE gene delivery clears circulating antibodies and tissue T-cell infiltration in a mouse model of autoimmune polyglandular syndrome type-1. Clin. Transl. Immunol. 2020;9:e1166.

    Not in our library10.1002/cti2.1166

  342. 342.

    Luo J., Luo Y., Sun J., Zhou Y., Zhang Y., Yang X. Adeno-associated virus-mediated cancer gene therapy: Current status. Cancer Lett. 2015;356:347-356.

    Not in our library10.1016/j.canlet.2014.10.045

  343. 343.

    WHO. Cancer.

    Not in our library

  344. 344.

    Kanazawa T., Mizukami H., Okada T., Hanazono Y., Kume A., Nishino H., Takeuchi K., Kitamura K., Ichimura K., Ozawa K. Suicide gene therapy using AAV-HSVtk/ganciclovir in combination with irradiation results in regression of human head and neck cancer xenografts in nude mice. Gene Ther. 2003;10:51-58.

    Not in our library10.1038/sj.gt.3301837

  345. 345.

    Kim J.Y., Kim J.H., Khim M., Lee H.S., Jung J.H., Moon D.H., Jeong S., Lee H. Persistent anti-tumor effects via recombinant adeno-associated virus encoding herpes thymidine kinase gene monitored by PET-imaging. Oncol. Rep. 2011;25:1263-1269.

    Not in our library10.3892/or.2011.1190

  346. 346.

    Mizuno M., Yoshida J., Colosi P., Kurtzman G. Adeno-associated Virus Vector Containing the Herpes Simplex Virus Thymidine Kinase Gene Causes Complete Regression of Intracerebrally Implanted Human Gliomas in Mice, in Conjunction with Ganciclovir Administration. Jpn. J. Cancer Res. 1998;89:76-80.

    Not in our library10.1111/j.1349-7006.1998.tb00482.x

  347. 347.

    Kojima Y., Honda K., Hamada H., Kobayashi N. Oncolytic gene therapy combined with double suicide genes for human bile duct cancer in nude mouse models. J. Surg. Res. 2009;157:e63-e70.

    Not in our library10.1016/j.jss.2008.12.016

  348. 348.

    Pan J.G., Zhou X., Luo R., Han R.F. The adeno-associated virus-mediated HSV-TK/GCV suicide system: A potential strategy for the treatment of bladder carcinoma. Med. Oncol. 2012;29:1938-1947.

    Not in our library10.1007/s12032-011-0091-x

  349. 349.

    Borel F., Kay M.A., Mueller C. Recombinant AAV as a platform for translating the therapeutic potential of RNA interference. Mol. Ther. J. Am. Soc. Gene Ther. 2014;22:692-701.

    Not in our library10.1038/mt.2013.285

  350. 350.

    Sun A., Tang J., Terranova P.F., Zhang X., Thrasher J.B., Li B. Adeno-associated virus-delivered short hairpin-structured RNA for androgen receptor gene silencing induces tumor eradication of prostate cancer xenografts in nude mice: A preclinical study. Int. J. Cancer. 2010;126:764-774.

    Not in our library10.1002/ijc.24778

  351. 351.

    Kota J., Chivukula R.R., O’Donnell K.A., Wentzel E.A., Montgomery C.L., Hwang H.W., Chang T.C., Vivekanandan P., Torbenson M., Clark K.R., et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell. 2009;137:1005-1017.

    Not in our library10.1016/j.cell.2009.04.021

  352. 352.

    Lu L., Luo S.T., Shi H.S., Li M., Zhang H.L., He S.S., Liu Y., Pan Y., Yang L. AAV2-mediated gene transfer of VEGF-Trap with potent suppression of primary breast tumor growth and spontaneous pulmonary metastases by long-term expression. Oncol. Rep. 2012;28:1332-1338.

    Not in our library10.3892/or.2012.1915

  353. 353.

    Wu Q.J., Gong C.Y., Luo S.T., Zhang D.M., Zhang S., Shi H.S., Lu L., Yan H.X., He S.S., Li D.D., et al. AAV-mediated human PEDF inhibits tumor growth and metastasis in murine colorectal peritoneal carcinomatosis model. BMC Cancer. 2012;12:129.

    Not in our library10.1186/1471-2407-12-129

  354. 354.

    Tse L.Y., Sun X., Jiang H., Dong X., Fung P.W., Farzaneh F., Xu R. Adeno-associated virus-mediated expression of kallistatin suppresses local and remote hepatocellular carcinomas. J. Gene Med. 2008;10:508-517.

    Not in our library10.1002/jgm.1180

  355. 355.

    Hunter J.E., Ramos L., Wolfe J.H. Viral Vectors in the CNS. Reference Module in Neuroscience and Biobehavioral Psychology. 2017.

    Not in our library10.1016/b978-0-12-809324-5.02446-9

  356. 356.

    Hermonat P.L., Quirk J.G., Bishop B.M., Han L. The packaging capacity of adeno-associated virus (AAV) and the potential for wild-type-plus AAV gene therapy vectors. FEBS Lett. 1997;407:78-84.

    Not in our library10.1016/s0014-5793(97)00311-6

  357. 357.

    Flotte T.R., Carter B.J. Adeno-Associated Viral Vectors. Gene Therapy Technologies, Applications and Regulations. 1999;109-125.

    Not in our library10.1002/0470842385.ch6

  358. 358.

    Verdera H.C., Kuranda K., Mingozzi F. AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer. Mol. Ther. J. Am. Soc. Gene Ther. 2020;28:723-746.

    Not in our library10.1016/j.ymthe.2019.12.010

  359. 359.
    Immunogenicity and toxicity of AAV gene therapy · 2022
    No notice
  360. 360.

    Fitzpatrick Z., Leborgne C., Barbon E., Masat E., Ronzitti G., van Wittenberghe L., Vignaud A., Collaud F., Charles S., Simon Sola M., et al. Influence of Pre-existing Anti-capsid Neutralizing and Binding Antibodies on AAV Vector Transduction. Mol. Ther. Methods Clin. Dev. 2018;9:119-129.

    Not in our library10.1016/j.omtm.2018.02.003

  361. 361.

    Denard J., Marolleau B., Jenny C., Rao T.N., Fehling H.J., Voit T., Svinartchouk F. C-reactive protein (CRP) is essential for efficient systemic transduction of recombinant adeno-associated virus vector 1 (rAAV-1) and rAAV-6 in mice. J. Virol. 2013;87:10784-10791.

    Not in our library10.1128/jvi.01813-13

  362. 362.

    Murphy S.L., Li H., Mingozzi F., Sabatino D.E., Hui D.J., Edmonson S.A., High K.A. Diverse IgG subclass responses to adeno-associated virus infection and vector administration. J. Med. Virol. 2009;81:65-74.

    Not in our library10.1002/jmv.21360

  363. 363.

    Mingozzi F., Meulenberg J.J., Hui D.J., Basner-Tschakarjan E., Hasbrouck N.C., Edmonson S.A., Hutnick N.A., Betts M.R., Kastelein J.J., Stroes E.S., et al. AAV-1-mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells. Blood. 2009;114:2077-2086.

    Not in our library10.1182/blood-2008-07-167510

  364. 364.

    Louis Jeune V., Joergensen J.A., Hajjar R.J., Weber T. Pre-existing anti-adeno-associated virus antibodies as a challenge in AAV gene therapy. Hum. Gene Ther. Methods. 2013;24:59-67.

    Not in our library10.1089/hgtb.2012.243

  365. 365.

    Wang L., Calcedo R., Bell P., Lin J., Grant R.L., Siegel D.L., Wilson J.M. Impact of pre-existing immunity on gene transfer to nonhuman primate liver with adeno-associated virus 8 vectors. Hum. Gene Ther. 2011;22:1389-1401.

    Not in our library10.1089/hum.2011.031

  366. 366.

    Herzog R.W., Biswas M. Neutralizing the Neutralizers in AAV Gene Therapy. Mol. Ther. 2020;28:1741-1742.

    Not in our library10.1016/j.ymthe.2020.07.015

  367. 367.

    Zengel J., Carette J.E. Structural and cellular biology of adeno-associated virus attachment and entry. Adv. Virus Res. 2020;106:39-84.

    Not in our library10.1016/bs.aivir.2020.01.002

  368. 368.

    Chowdhury E.A., Meno-Tetang G., Chang H.Y., Wu S., Huang H.W., Jamier T., Chandran J., Shah D.K. Current progress and limitations of AAV mediated delivery of protein therapeutic genes and the importance of developing quantitative pharmacokinetic/pharmacodynamic (PK/PD) models. Adv. Drug Deliv. Rev. 2021;170:214-237.

    Not in our library10.1016/j.addr.2021.01.017

  369. 369.

    Kang L., Jin S., Wang J., Lv Z., Xin C., Tan C., Zhao M., Wang L., Liu J. AAV vectors applied to the treatment of CNS disorders: Clinical status and challenges. J. Control. Release. 2023;355:458-473.

    Not in our library10.1016/j.jconrel.2023.01.067

  370. 370.

    Colle M.A., Piguet F., Bertrand L., Raoul S., Bieche I., Dubreil L., Sloothaak D., Bouquet C., Moullier P., Aubourg P., et al. Efficient intracerebral delivery of AAV5 vector encoding human ARSA in non-human primate. Hum. Mol. Genet. 2010;19:147-158.

    Not in our library10.1093/hmg/ddp475

  371. 371.

    Zerah M., Piguet F., Colle M.A., Raoul S., Deschamps J.Y., Deniaud J., Gautier B., Toulgoat F., Bieche I., Laurendeau I., et al. Intracerebral Gene Therapy Using AAVrh.10-hARSA Recombinant Vector to Treat Patients with Early-Onset Forms of Metachromatic Leukodystrophy: Preclinical Feasibility and Safety Assessments in Nonhuman Primates. Hum. Gene Ther. Clin. Dev. 2015;26:113-124.

    Not in our library10.1089/humc.2014.139

  372. 372.

    Zieger M., Borel F., Greer C., Gernoux G., Blackwood M., Flotte T.R., Mueller C. Liver-directed SERPINA1 gene therapy attenuates progression of spontaneous and tobacco smoke-induced emphysema in α1-antitrypsin null mice. Mol. Ther. Methods Clin. Dev. 2022;25:425-438.

    Not in our library10.1016/j.omtm.2022.04.003

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