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Nerve growth factor: from the early discoveries to the potential clinical use

Luigi Aloe, Maria Luisa Rocco, Patrizia Bianchi and 1 more

Journal of Translational Medicine · 2012 · Review

Abstract

The physiological role of the neurotrophin nerve growth factor (NGF) has been characterized, since its discovery in the 1950s, first in the sensory and autonomic nervous system, then in central nervous, endocrine and immune systems. NGF plays its trophic role both during development and in adulthood, ensuring the maintenance of phenotypic and functional characteristic of several populations of neurons as well as immune cells. From a translational standpoint, the action of NGF on cholinergic neurons of the basal forebrain and on sensory neurons in dorsal root ganglia first gained researcher’s attention, in view of possible clinical use in Alzheimer’s disease patients and in peripheral neuropathies respectively. The translational and clinical research on NGF have, since then, enlarged the spectrum of diseases that could benefit from NGF treatment, at the same time highlighting possible limitations in the use of the neurotrophin as a drug. In this review we give a comprehensive account for almost all of the clinical trials attempted until now by using NGF. A perspective on future development for translational research on NGF is also discussed, in view of recent proposals for innovative delivery strategies and/or for additional pathologies to be treated, such as ocular and skin diseases, gliomas, traumatic brain injuries, vascular and immune diseases.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

Nerve growth factor

1Nerve growth factor (NGF) is the first discovered member of the neurotrophin family. NGF is essential for the development and phenotypic maintenance of neurons in the peripheral nervous system (PNS) and for the functional integrity of cholinergic neurons in the central nervous system (CNS) (Figure 1). The amino acid and messenger RNA sequences of this neurotrophin have been classified and indicate that NGF is a highly conserved molecule that shares considerable homology within different species. The mature, active form of NGF descend from proteolitic cleavage of a precursor form (ProNGF), that have important roles during development and in adult life, having both pro-apoptotic and neurotrophic properties.

2NGF exerts its biological action by challenging the specific receptor tropomyosin kinase receptor A (TrkA), which is a typical tyrosine kinase receptor. The major cytosolic/endosomal pathways activated by the TrkA are Ras-mitogen activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K) -Akt, and Phospholipase C (PLC) -γ. NGF also binds to and activate the low-affinity, non-selective p75 pan-neurotrophin receptor (p75NTR). This receptor is a transmembrane glycoprotein that regulates signaling through TrkA; binding of NGF to p75NTR activates additional signaling pathways that, in the absence of co-expressed TrkA, may signal a cell to die via apoptosis. Signaling pathways activated by p75NTR are the Jun kinase signaling cascade, NF-κB and ceramide generation.

3The discovery of NGF dated the ‘50s of the last century and was awarded with the Nobel prize in 1986. In 1953, Rita Levi-Montalcini, working in the Victor Hamburger laboratory at Washington University (Saint Louis, MA, USA), grafted a piece of mouse sarcoma tissue onto chick embryos whose wing buds had been extirpated. She discovered that the tumor tissue produced a soluble factor that promoted the growth of nearby sensory and sympathetic ganglia. Collaborating with the biochemist Stanley Cohen, they isolated the substance responsible and named it NGF. For over 35 years, NGF has been considered as a very powerful and selective growth factor for sympathetic and sensory neurons and for cells derived from the neuronal crest (Figure 2). In these neurons, NGF dynamically controls neurotransmitters and neuropeptides synthesis. In sympathetic neurons the production of norepinephrine is regulated by NGF through selective induction of tyrosine hydroxylase (TH). In the dorsal root ganglion (DRG) the expression of neuropeptides such as Substance P (SP) and Calcitonin Gene-Related Peptide (CGRP) by primary sensory neurons is under NGF control and in vivo deprivation of NGF, as a result of nerve transection or anti-NGF treatment, causes a marked decrease in SP and CGRP synthesis. NGF supply from the innervation field influences the neuronal plasticity that allows the adult nervous system to modify its structure and functions in response to stimuli. Indeed, the constitutive synthesis of NGF in adult tissues correlates with PNS neurons phenotypic features, such as innervation density, cell body size, axonal terminal sprouting, dendrites arborization, induction or inhibition of neuropeptides and neurotransmitters or transmitter-producing enzymes.

4In the central nervous system (CNS), the greatest amount of NGF is produced in the cortex, the hippocampus and in the pituitary gland; although significant quantities of this neurotrophin are also produced in other areas, including the basal ganglia, thalamus, spinal cord and in the retina. The NGF plays a pivotal role in the survival and function of cholinergic neurons of the basal forebrain complex (BFC) (Figures 1 and 2), such functions include attention, arousal, motivation, memory and consciousness. Since BFC neurons are highly affected in Alzheimer’s disease (AD), NGF has been indicated as a potential protective and/or curative factor for neurodegenerative disorders associated with these neurons. In the CNS, NGF also regulates phenotypic features in noradrenergic nuclei of hypothalamus and brainstem, participating in the central regulation of autonomic response and in the modulation of stress axis activity.

5Cells of the immune-hematopoietic system also produce and utilize NGF. Since the early description of the effects of NGF on mast cells (Figures 1 and 2), the role played by the neurotrophin in the regulation of immune functions and immune cells' behavior has been greatly characterized. NGF receptors are expressed in immune organs and on immune cell populations (Figure 1) allowing NGF to modulate cell differentiation and regulate the immune response. NGF affects the survival and/or differentiation and/or phenotypic features of hematopoietic stem cells, granulocytes, lymphocytes and monocytes. NGF concentrations in the tissues change during inflammation and inflammatory mediators induce NGF synthesis in a variety of cell types. Enhanced production of NGF has been reported in inflamed tissues of patients with inflammatory and autoimmune diseases, but the reasons why NGF concentration is enhanced and how this can affect inflammatory responses are far from being fully understood.

Peripheral neuropathies

6According to the classical neurotrophic model, NGF is produced in and released by target tissues, is then captured by specific receptors expressed on nerve terminals and retrogradely transported to the neuron body, where it exerts its neurotrophic activity. Any perturbation in the neurotrophic circuit could generate peripheral nerve dysfunction and neuronal sufferance, as those characterizing peripheral neuropathies. Data obtained in animal models and in human pathologies demonstrated that disease-associated peripheral neuropathies could be associated with either deregulation of NGF synthesis, transport and utilization by PNS neurons. This gives to NGF an etiological value in the development of neuropathic symptoms associated with, i.e., diabetes, HIV infections or chemotherapy, and point to the neurotrophin as a possible pharmacological tool in the treatment of peripheral neuropathies (see Table 1 for a comprehensive summary of clinical trials on NGF in peripheral neuropathies).

Diabetes

7Diabetes is often characterized by major complications such as dysfunction and degeneration of several types of PNS neurons/fibers. Sensory involvement is predominant, the small diameter sensory fiber degeneration being responsible for the more debilitating symptoms. Deficits of NGF transport, serum and tissue content have been demonstrated in experimental diabetes. Major components of the NGF signaling pathway have been also found deregulated in experimental diabetes, as well as the production of neuromodulators that is known to be under NGF control. On the other hand NGF supply in animal models of diabetic neuropathies reverses neuropathic signs, by protecting the affected PNS neurons and normalizing their activity.

8The production of recombinant human NGF (rhNGF) has been first developed and tested in phase I clinical trial, where moderate side effects, such as myalgias and injection site hyperalgesia, were evidenced in healthy subjects. A phase II clinical trial on 250 patients affected by diabetic polyneuropathy was then performed. The study revealed a significant improvement of neuropathic symptoms in the NGF-treated patients, but also evidenced the occurrence of side effects, such as injection site hyperalgesia, myalgias and arthralgias, that limited the blinding of the study. The results of the study were, however, considered encouraging and clinical trial continued in a phase III study. Those enrolled 1019 patients who were treated subcutaneously with rhNGF, 3 times a week for 48 weeks. The study revealed almost the same side effects of the previous ones, but failed to demonstrate substantial benefits from the NGF treatment. The relative failure of the study, compared to previous phase II trial, was attributed to the low dosage, limited by the occurrence of side effects, but other causes, as the characteristic of patient population, choice of end points, measurement of neuropathy and the possible low quality of the rhNGF used, were not excluded.

Human immunodeficiency virus

9Peripheral nerve complications in human immunodeficiency virus (HIV) patients could arise from the virus itself or from the anti-viral drugs. A phase II, multicenter, placebo-controlled, randomized clinical trial with subcutaneous rhNGF on 270 HIV-infected patients affected by sensory neuropathy has been performed a decade ago. A significant positive effect of rhNGF was found on neuropathic pain, with injection site pain as the most frequent side effect. It was concluded that rhNGF was safe and well tolerated. In contrast with the latter study, the same group published a report on the long-term (48 weeks) effect of rhNGF in an open-label study of 200 subjects with HIV-associated distal sensory neuropathy. While apparently safe and well tolerated, the NGF did not improve the severity of neuropathy, measured by neurological examination, quantitative sensory testing and epidermal nerve fiber density.

Other peripheral neuropathies that could benefit from NGF treatment

10In vitro and in vivo studies provided support for clinical trials on rhNGF in chemotherapy-induced peripheral neurotoxicity (CIPN). The development of sensory neuropathies often limits the dosage and time-extension of anti-tumor therapies based on cytotoxic agents. NGF has been demonstrated to counteract the reduction of neurite outgrowth from rat DRG in vitro, induced by cisplatin, vincristine or Taxol and the development of behavioral manifestations of cisplatin-induced neuropathy. Moreover, a positive correlation was found between the decrease of circulating NGF and the severity of CIPN in humans.

11A decrease in NGF has been also reported in leprosy-affected human skin and nerve. The NGF produced by keratinocytes has been found decreased in skin biopsies from leprosy patients. Moreover, a significant loss of intra-epidermal innervation, and a lowered expression of sensory neuromodulators that are under NGF control, such as Substance P and the sodium channel SNS/PN3, have been found in leprosy-affected skin. From a clinical standpoint all these NGF system alterations found in leprosy skin correlated with the characteristic sensory deficit and the loss of skin neurotrophism that might lead to trophic ulcers and mutilation.

CNS diseases

12Studies on rodents and primates have demonstrated that exogenous NGF was able at neuro-protecting BFC neurons by both traumatic insults and age-related cholinergic decline. It has also been demonstrated that NGF could directly act on two classical hallmark of AD: β-amyloid neurotoxicity and tau hyperphosphorylation. Indeed in vitro and in vivo experiments indicated NGF as a direct anti-amyloidogenic factor, being able to regulate both amyloid gene expression and protein processing. Furthermore NGF has been shown to counteract tau hyperphosphorylation both in vitro and in vivo. Further studies on human tissues failed to demonstrate a reduction of NGF production in the cortex and hippocampus of AD patients, while the evidence for a decreased NGF immunoreactivity in the BFC suggested that impaired NGF supply via retrograde transport could be the effective cause of cholinergic neurodegeneration in AD. Thus, the correct therapeutic strategy should pursue NGF deliverance in the proximity of cholinergic cell bodies, where the effective NGF deficits have been revealed, rather than in axon terminal regions (i.e. cortex and hippocampus).

13The greatest challenge in the delivery of NGF to CNS resides in its inability in crossing the blood–brain barrier (BBB), when systemically administered. For this reason, the intra-cerebro-ventricular (ICV) way of NGF delivery has been pursued in AD patients in two separate clinical trials (see Table 2 for a summary of NGF clinical trials in CNS disease). In the first study, a single patient was treated with murine NGF (mNGF) infusion into the right ventricle. The treatment resulted in a marked transient increase in uptake and binding of 11C] -nicotine in the frontal and temporal cortex, a persistent increase in cortical blood flow and a progressive decrease of slow wave EEG activity Tests of verbal episodic memory were also improved whereas other cognitive tests were not. As relevant side effect, weight loss was reported. The results of a second study on ICV mNGF delivery was published in 1998. The relative positive outcomes found in the first study were confirmed in the two patients treated with higher doses of mNGF. However, the major finding of the study could be considered the occurrence of important and severely limiting side effects: reversible weight loss during the mNGF infusion period and, most importantly, development of back pain symptoms after the beginning of ICV infusion that most probably reflects the NGF-mediated hyper-activation of nociceptive transmission system in the spinal cord. These side effects were considered to outweigh the positive outcomes and lead to discontinuation of ICV infusion-based trials in AD patients.

14The ICV NGF infusion has been also pursued in single or small groups of patients in diseases such as Parkinson’s disease (PD) and hypoxic-ischemic perinatal brain injury. The rationale for the use of NGF infusion in PD is linked to its supportive role for adrenal medullary cells engrafted in the basal ganglia of PD patients. The cell replacement therapy for PD patients by autologous chromaffin adrenal tissue grafting into the caudate nucleus was pursued in the 1980’s, and based on previous positive indications coming from animal studies on models of PD. Overall, these studies lead to consensus over the lack of long-lasting effects, due to lack of specific support to engrafted cells. NGF ICV infusion was then attempted, in light of NGF effects on survival, neurite outgrowth, and functionality of grafts of adrenal chromaffin cells to the basal ganglia. The study reports the case of a 63 year-old patient that underwent autologous graft of adrenal medulla into the putamen, supported by a 23 day ICV infusion of mNGF. During the 13 months follow up the patient had a rapid decrease in rigidity and hyperkinesias that was similar to what observed in previous studies on autologous graft of chromaffin tissue in PD patients. The specific effect of mNGF support to the graft was identified in a slower improvement of motor functions that was extended for 11 months after the graft procedure. Thus NGF treatment could prolong the effect of adrenal chromaffin grafts in human PD.

15As for the clinical studies performed on children with traumatic brain injury (TBI), the rationale for NGF utilization comes from animal studies, showing that NGF can reduce neurological deficits following brain injury in animals, and from the observation that NGF levels in the cerebro-spinal fluid (CSF) of TBI patients have a positive correlation with neurological outcomes. Two studies were attempted with an ICV infusion of mNGF in children with TBI. In the first study two infants aged 8 and 9 months were treated with mNGF infused into the right cerebral ventricle for 10 days starting 30 days after the hypoxic-ischemic brain injury. Very preliminary observations detected an improvement in the comatose status, increased alpha/theta ratio in the EEG, reduction of malacic areas and improvement, in one child only, of the regional cerebral perfusion in right temporal and occipital cortices, as measured by SPECT. A second study in 2 infants aged 8 and 13 months and affected by hypoxic-ischemic brain damage, showed the results of mNGF ICV infusion, starting 4 months after TBI. Again, an improvement in EEG and SPECT parameters was scored with a concomitant increase of doublecortin, a protein expressed by newly formed neurons, in the CSF. These studies, tough limited by a small number of patients, indicated a possible effect of NGF in the treatment of TBI secondary to hypoxic-ischemic brain insult, but did not investigate potential side effects linked to the ICV infusion.

Skin ulcers

16Beside its action as a neurotrophic factor for nerve cells, NGF has been characterized as a regulatory factor for many non-neuronal cell types, expressing NGF receptors. The role of NGF on skin biology is particularly relevant from a clinical perspective. Production and utilization of NGF has been demonstrated in skin cells, as keratinocytes, and in immune cells that are resident or recruited in epidermal tissue following trauma or inflammation. NGF deregulation has been described in diseased skin. The effects of NGF on the healthy and diseased skin could be directly exerted via NGF receptors expressed on epidermal and dermal cells, or by NGF influence on PNS skin innervation that is known to regulate skin homeostasis by neuropeptides and neurotransmitter release. The possible role of NGF as a therapeutic in skin trauma and/or diseases was investigated in animal models of wound healing. Later on, topical application of NGF has been pursued in several forms of epithelial derangements and skin disease (summarized in Table 3).

17Topical mNGF has been applied in three diabetic patients affected by on foot ulcers. The treatment induced a local progressive restoration of nerve function and an almost complete relapse of ulcers within 5–14 weeks since the beginning of treatment.

18Another clinical study was performed in patients affected by chronic vasculitic ulcers secondary to rheumatoid arthritis (RA) or systemic sclerosis (SSc). The leg ulcers of the patients with rheumatoid arthritis (n=4) showed a rapid reduction in volume which led, in all cases, to heal within 5–8 weeks. Descriptive variables such as pain, presence of granulation, absence of inflammation also improved in the same period. SSc patients (n=4) were treated on both the hand and leg ulcers. Despite little improvement in inflammatory states and ulcer size, none of the ulcers reached healing after 8 weeks. The authors speculated over the different effects in RA and SSc ulcers as attributable to disease features diversity, especially in the microvascular fibrosis that characterizes SSc and could reduce NGF access to damaged cells.

19Pressure ulcers have been also treated with topical mNGF and results reported in two separate studies from the same group. The first study described a single patient affected by pressure ulcers bilaterally located on the elbows. The right elbow was treated with mNGF and the ulcer was reduced by 1/3 while the left elbow ulcer was substantially unchanged. In the second report, a randomized, double-blind, placebo-controlled trial was described, aimed at investigating the effects of topical treatment with mNGF in patients with severe, non-infected pressure ulcers of the foot. Topical mNGF was applied to 18 patients, while another 18 patients received vehicle treatment only. The average reduction in pressure ulcer area after 6-week follow-up period was statistically significantly greater in the treatment group than in the control group.

20Another interesting case report investigated the effect of topical NGF treatment in ischemic skin revascularization. In this case the described effects of NGF as a promoter of vascular-endothelial growth factor (VEGF) and neo-vascularization gave the rationale background for treatment of a child with a severe crush syndrome of the lower left limb with subcutaneous mNGF. The gradual improvement of the ischemic treated area was observed throughout the treatment period, with a significant reduction in size of the overall ischemia and a final outcome identified in a reduction of the area that finally underwent calcaneal escharotomy. It is worth noticing that the pro-angiogenic activity of NGF could be of therapeutic relevance in various types of cancer, where positive correlations between cancer stage/prognosis and tissue NGF levels have been described. Thus, targeting the NGF/VEGF interaction system should be also regarded as a potential new strategy for anti-angiogenic therapy against cancer as well as for other angiogenesis-dependent diseases, such as diabetes, and arthritis.

Ophthalmology

21The use of NGF as a therapeutic in ophthalmology is perhaps the best characterized and developed, among the other possible or yet pursued clinical use (refer to Table 4 for a summary of clinical trials of NGF in ophthalmology). One of the first evidence suggesting a possible role of NGF in the visual system was reported in 1979 by Turner who showed that the retinal cells of goldfish are receptive to the action of NGF. It has been reported that NGF induces modification of pre-synaptic elements in adult visual system, prevents the shift in ocular dominance distribution of visual cortical neurons and promotes functional recovery of retinal ganglion cells (RGC) after ischemia, delays retinal degeneration in rodents with inherited retinopathy, reduces retinal damages in rabbits with ocular hypertension, while injection of antibody against NGF exacerbate the damaging effect on RGC. The first attempt to translate preclinical studies into clinic was based on the described presence of NGF and NGF receptors on corneal cells and structure, suggesting a possible trophic influence of the neurotrophin on the ocular surface.

22In the first published study about the application of NGF-eyedrops, severe corneal ulcers associated with anesthesia (corneal neurotrophic keratitis) were treated with purified mNGF. The results reported a rapid healing of all of the ulcers, improved corneal sensitivity and integrity and improved visual acuity. Very similar results were reported in a following study, on neurotrophic keratitis non-responsive to conventional treatments. The follow-up lasted for a period ranging between 3 and 32 months after initiation of treatment and the study shows that all patients achieved complete healing of the corneal defect within a period between 12 days and 6 weeks after initiation of treatment. The study also showed that the occurrence of side effects, described as hyperemia and moderate pain in the eye and periocular area, were well tolerated and limited to the time necessary for the remission of corneal keratitis.

23A study published in 2007 evaluated the effect of topical treatment with mNGF on eyes from 11 patients with neurotrophic keratopathy, considering in particular the possible occurrence of unpleasant side effects and the development of systemic anti-NGF as a result of the treatment protocol. All patients had healing of corneal ulcers between 9 and 43 days after initiation of treatment. The study revealed that the ocular discomfort lasted less than an hour after the instillation of eye drops and that any painful sensation disappeared, even when NGF treatments were continued after the healing of corneal ulcers. None of the patients developed systemic symptoms during treatment or during follow-up. The presence of antibodies against the mNGF in the blood was negative for all of the treated patients during the therapy and for a period of follow-up up to 72 months.

24After the first approach on ocular surface pathologies, mNGF was used in clinical studies addressing the posterior segment of the eye. In a study published in 2009, the application of topical mNGF, was evaluated in three patients with advanced glaucoma, with imminent risk of loss of visual function. The reported results were: progressive improvement in the functionality of the inner retinal layer and in the parameters of the post-retinal neural conduction, evident during the treatment period and maintained even 3 months after discontinuation of treatment; visual acuity improved significantly in all patients where it remained unchanged for the 3-month follow-up. The study also showed the substantial absence of side effects, except for the development of local burning during the first week of treatment in a single patient.

25Another case report was about the use of topical mNGF to treat a patient suffering from bilateral macular degeneration (AMD). The treatment was continued for 6 years virtually uninterrupted. Checks were made on a quarterly basis and showed a clinical (improvement of visual acuity) and electrofunctional (increasing the amplitude of the ERG) improvements in the right eye, correlated with treatment. The only side effect noted was a sensation of slight burning at the time of application of eye drops during the first month of treatment.

26It is worth noticing that in none of the cited studies systemic side effects attributable to the biological action of NGF itself were reported. In particular, the ocular NGF seems not to give rise to systemic effects on the perception of pain (myalgias, hyperalgesia) reported in clinical trials with systemic or intra-cerebroventricular administration.

Novel delivery routes

27Though applied to a wide spectrum of neurological and non-neurological diseases, clinical utilization of NGF, especially when systemically administered, remains hampered by important adverse events, such as those derived from the effects of NGF on pain system. Moreover, the achievement of pharmacological concentrations in therapeutic relevant targets without affecting non-target areas represents a further delivery challenge.

28A potential approach to overcome such limitations is represented by gene therapy. Preclinical data obtained in rodents and primates indicated that ex vivo gene therapy targeted at BFC neurons were effective in improving experimentally induced cholinergic deficits. A phase I clinical trial has been performed on 8 AD’s patients, in which autologous fibroblasts were engineered to produce and secrete human NGF (hNGF) and implanted into the BFC (Table 2). Positive outcomes in behavioral scales were scored in two out of six patients that survived cell implant neurosurgery in a period ranging from six to eighteen months after implant, associated with improvement in PET scans. A second phase I trial based on in vivo NGF gene delivery, by adeno-associated virus vector (CERE-110) has been set-up in 2004 (Table 2). The phase I study was a dose-escalating study to assess the safety and tolerability of CERE-110 in subjects with mild to moderate AD’s. CERE-110 has passed phase I clinical testing and a multicenter phase II clinical trial has commenced. In addition to the CERE-110 trial, a new, cell-based in vivo delivery system has been developed and a Phase I trial has been registered by Karolinska Institute in Sweden on AD’s patients (Table 2). This delivery system is based on human retinal pigment epithelial cell line, engineered to secrete hNGF and encapsulated within a polymer membrane that is part of an implantable catheter-like device, and has been demonstrated to effectively prevent the loss of cholinergic neurons after fimbria transection in rats. The results of the first safety and tolerability study based on such system have been recently published, demonstrating that surgical implantation and removal of devices containing NGF-secreting cells in the basal forebrain of AD patients are feasible, well tolerated and relatively safe, and that they do not generate NGF-related adverse events. Though the system remains to be optimized in terms of long-term function of implanted cells and in the achievement of positive neurological outcomes (actually limited to 2 out of 6 patients), it seems to present advantages over other gene delivery approaches, since it allows the safe removal of engineered cells as well as their immune isolation from host tissues, thus protecting the allogeneic transplanted cells from host immune system rejection.

29The olfactory pathway is a promising, non-invasive route for drug delivery to the brain, which has potential for the treatment of neurodegenerative diseases. The BBB represents one of the major obstacles in drug development for brain diseases and many studies have focused on the possibility of circumventing the BBB for the direct central delivery of macromolecules to the central nervous system by utilizing the potential direct transport pathway from nose to brain via the olfactory region. The intranasal delivery of NGF to the brain could indeed represent a non-invasive and safe route to achieve relevant therapeutic concentration of NGF in selected brain areas, without eliciting undesired and adverse side effects. The characterization of pharmacokinetic for intranasal delivery of NGF revealed that intranasal NGF rapidly spread through brain tissue without significant increasing NGF concentrations in the CSF and in the blood. Studies on animal models of AD, revealed that intranasal NGF, while exerting specific therapeutic actions on the affected cholinergic system, did not provide trophic support to sympathetic ganglia, nor did it induced the over expression of nociception neuromodulators, such as sensory neuropeptides, known to be under NGF control. Recent studies published by the same group, characterized a form of hNGF mutated at residue R100, testing it both in vitro and in vivo, by intranasal delivery, in an animal model of AD. Such a mutated hNGF retains the neurotrophic potential of the native NGF, without eliciting pain-related response. It would be of interest whether such a “painless” NGF variant can be validated in preclinical and hopefully future clinical trials for neurodegenerative diseases.

30Another actually investigated route that seems to be able to deliver NGF to the brain in a safe and effective manner is the topical administration of NGF on ocular surface. Animal studies have demonstrated that NGF applied on the ocular surface can reach central cholinergic neurons, which are affected in AD. Moreover, ocular NGF is able to activate c-fos in several areas of the limbic system in a time-dependent manner and to enhance the distribution of Ki67positive cells also expressing p75NTR in the proliferating layer of the sub-ventricular zone, indicating that ocular NGF can activate the machinery regulating the proliferation and maturation of neuronal precursor in the brain. Compared to intranasal delivery, the intraocular one appears to be less characterized, in terms of mechanisms and anatomical route for brain delivery. The available data indicate that the ocular delivered NGF does not induce systemic side effects related to the systemic NGF administration, even when this is repeated for rather long time periods, being able to target selected brain areas. In a recent study on a mouse model of AD the intranasal and ocular delivery routes for hNGF administration were compared for their relative diffusion in the systemic compartment in concentration that could elicit a pain response. The authors reported that intra-nasally applied hNGF was safer when compared to intra-ocular one. It should however be taken into consideration and tested whether there is a possible different biological activity of mNGF used in the majority of the ophthalmology clinical trials versus the rhNGF used in the cited comparative study.

31To date two reports, both from the same group, investigated the clinical effects of topical ocular NGF on brain structures lying behind the retina (Table 2). In one study five pediatric patients with optic gliomas (OGs) and advanced optic nerve atrophy were assessed before and after a single 10 day course of 1 mg (total) mNGF topical administration by clinical evaluation, visual evoked potentials (VEPs), and brain magnetic resonance imaging (MRI). While not affecting tumor size, the topical mNGF improved VEPs suggesting a visual rescuing mechanism exerted by mNGF on the residual viable optic pathways. In a further study a single adult patient with OG and long-standing optic nerve atrophy was treated with mNGF and the follow-up was performed by clinical, neuroradiologic, and electrophysiological tests (electroretinogram and VEPs) at the end of each treatment and 30 and 60 days later. Repeated subjective and objective improvement of visual function was recorded after mNGF treatment, which tended to deteriorate toward baseline values 60 days from the end of each mNGF treatment. Interestingly, no ocular or systemic side effects were observed throughout treatment.

Conclusions

32Soon after its discovery, in the middle of the twentieth century, it became clear that NGF had great pharmacological potentialities, for the treatment of major central neurodegenerative diseases and of peripheral neuropathies. After preclinical characterization and clinical trials have been performed by treating AD, Parkinson’s, and diabetic patients (Figure 2, Tables 1 and 2), severe limitations in the clinical use of NGF emerged, coming from its physiological action on the sensory and autonomic systems and from the high pharmacological doses needed to obtain disease improvements. Despite the discouraging results coming from trials mainly performed across the 1990’s, the translational research on NGF was not stopped, widening the spectrum of diseases that could benefit from NGF-based therapy and investigating new delivery strategies, aimed at maximizing positive outcomes and limiting or fully circumventing the deleterious side effects described in earlier clinical trials. Today we know that epithelial derangements based on poor neurotrophism could be safely treated with topical NGF, while a wide spectrum of CNS and PNS diseases will probably benefit from NGF therapy, once intranasal or gene delivery systems will be finally set-up and fully translated into clinical practice. A further challenge, in conclusion, is represented by the increasing knowledge on the role of NGF in immune system regulation, opening a promising field for development of innovative NGF-based therapies in the care of, in example, chronic inflammatory or autoimmune diseases, and a novel and challenging aspect in the NGF saga.

Abbreviations

33AD: Alzheimer’s disease; BBB: Blood–brain barrier; BFC: Basal forebrain complex; CGRP: Calcitonin gene-related peptide; CIPN: Chemotherapy-induced peripheral neurotoxicity; CNS: Central nervous system; CSF: Cerebro-spinal fluid; DRG: Dorsal root ganglion; ERK: Extracellular signal-regulated kinase; HIV: Human immunodeficiency virus; hNGF: Human NGF; ICV: Intra-cerebro-ventricular; MAPK: Mitogen activated protein kinase; mNGF: Murine NGF; MRI: Magnetic resonance imaging; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NGF: Nerve growth factor; OG: Optic glioma; p75NTR: p75 pan-neurotrophin receptor; PD: Parkinson’s disease; PI3K: Phosphatidylinositol 3-kinase; PLC: Phospholipase C; PNS: Peripheral nervous system; RA: Rheumatoid arthritis; RGC: Retinal ganglion cell; rhNGF: Recombinant human NGF; SP: Substance P; SSc: Systemic sclerosis; TBI: Traumatic brain injury; TH: Tyrosine hydroxylase; TrkA: Tropomyosin kinase receptor A; VEGF: Vascular-endothelial growth factor; VEPs: Visual evoked potentials.

Competing interests

34The authors declare that they have no competing interests.

Authors’ contributions

35LA conceived, drafted and reviewed the manuscript. MLR drafted and reviewed the manuscript. PB drafted and reviewed the manuscript. LM conceived, drafted and reviewed the manuscript. All authors read and approved the final manuscript.

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14.
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Not in our library10.1146/annurev.neuro.24.1.551
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Not in our library10.1111/j.1440-1681.1997.tb02089.x
16.
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Not in our library10.1515/revneuro.1993.4.1.41
17.
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Mearow KM Kril Y Anti-NGF treatment blocks the upregulation of NGF receptor mRNA expression associated with collateral sprouting of rat dorsal root ganglion neuronsNeurosci Lett1995 184555855-58
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Verge VM Richardson PM Wiesenfeld-Hallin Z Hokfelt T Differential influence of nerve growth factor on neuropeptide expression in vivo: a novel role in peptide suppression in adult sensory neuronsJ Neurosci1995 1520812096
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20.
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21.
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Aloe L Alleva E De Simone R Changes of NGF level in mouse hypothalamus following intermale aggressive behaviour: biological and immunohistochemical evidenceBehav Brain Res1990 395361
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27.
Taglialatela G Angelucci L Scaccianoce S Foreman PJ Perez-Polo JR Nerve growth factor modulates the activation of the hypothalamo-pituitary-adrenocortical axis during the stress responseEndocrinology1991 12922122218
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Scaccianoce S Cigliana G Nicolai R Muscolo LA Porcu A Navarra D Perez-Polo JR Angelucci L Hypothalamic involvement in the activation of the pituitary-adrenocortical axis by nerve growth factorNeuroendocrinology1993 58202209
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30.
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Not in our library10.1076/apab.109.4.354.4235
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34.
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36.
Cattoretti G Schiro R Orazi A Soligo D Colombo MP Bone marrow stroma in humans: anti-nerve growth factor receptor antibodies selectively stain reticular cells in vivo and in vitroBlood1993 8117261738
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37.
Chevalier S Praloran V Smith C MacGrogan D Ip NY Yancopoulos GD Brachet P Pouplard A Gascan H Expression and functionality of the trkA proto-oncogene product/NGF receptor in undifferentiated hematopoietic cellsBlood1994 8314791485
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38.
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Burgi B Otten UH Ochensberger B Rihs S Heese K Ehrhard PB Ibanez CF Dahinden CA Basophil priming by neurotrophic factors. Activation through the trk receptorJ Immunol1996 15755825588
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41.
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Takafuji S Bischoff SC De Weck AL Dahinden CA Opposing effects of tumor necrosis factor-alpha and nerve growth factor upon leukotriene C4 production by human eosinophils triggered with N-formyl-methionyl-leucyl-phenylalanineEur J Immunol1992 22969974
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45.
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48.
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49.
Melamed I Kelleher CA Franklin RA Brodie C Hempstead B Kaplan D Gelfand EW Nerve growth factor signal transduction in human B lymphocytes is mediated by gp140trkEur J Immunol1996 2619851992
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50.
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Not in our library10.1073/pnas.86.24.10059
51.
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Not in our library10.1016/s0092-8674(00)81113-7
52.
Ehrhard PB Erb P Graumann U Otten U Expression of nerve growth factor and nerve growth factor receptor tyrosine kinase Trk in activated CD4-positive T-cell clonesProc Natl Acad Sci USA1993 901098410988
Not in our library10.1073/pnas.90.23.10984
53.
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Noga O Peiser M Altenahr M Knieling H Wanner R Hanf G Grosse R Suttorp N Differential activation of dendritic cells by nerve growth factor and brain-derived neurotrophic factorClin Exp Allergy2007 3717011708
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55.
Caroleo MC Costa N Bracci-Laudiero L Aloe L Human monocyte/macrophages activate by exposure to LPS overexpress NGF and NGF receptorsJ Neuroimmunol2001 113193201
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Ehrhard PB Ganter U Stalder A Bauer J Otten U Expression of functional trk protooncogene in human monocytesProc Natl Acad Sci USA1993 9054235427
Not in our library10.1073/pnas.90.12.5423
57.
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59.
Thorpe LW Stach RW Hashim GA Marchetti D Perez-Polo JR Receptors for nerve growth factor on rat spleen mononuclear cellsJ Neurosci Res1987 17128134
Not in our library10.1002/jnr.490170206
60.
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Not in our library10.1016/j.semarthrit.2009.03.002
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Not in our library10.2174/187152810792231913
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Not in our library10.1016/s0079-6123(03)46023-8
63.
Linker R Gold R Luhder F Function of neurotrophic factors beyond the nervous system: inflammation and autoimmune demyelinationCrit Rev Immunol2009 294368
Not in our library10.1615/critrevimmunol.v29.i1.20
64.
Yuen EC Howe CL Li Y Holtzman DM Mobley WC Nerve growth factor and the neurotrophic factor hypothesisBrain Dev1996 18362368
Not in our library10.1016/0387-7604(96)00051-4
65.
Mendell LM Neurotrophin action on sensory neurons in adults: an extension of the neurotrophic hypothesisPain1999 Suppl 6S127S132
Not in our library10.1016/s0304-3959(99)00146-3
66.
Hellweg R Hartung HD Endogenous levels of nerve growth factor (NGF) are altered in experimental diabetes mellitus: a possible role for NGF in the pathogenesis of diabetic neuropathyJ Neurosci Res1990 26258267
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Not in our library10.1006/exnr.1994.1181
68.
Apfel SC Kessler JA Neurotrophic factors in the therapy of peripheral neuropathyBaillieres Clin Neurol1995 4593606
Not in our library
69.
McMahon SB Priestley JV Peripheral neuropathies and neurotrophic factors: animal models and clinical perspectivesCurr Opin Neurobiol1995 5616624
Not in our library10.1016/0959-4388(95)80067-0
70.
Anand P Neurotrophins and peripheral neuropathyPhilos Trans R Soc Lond B Biol Sci1996 351449454
Not in our library10.1098/rstb.1996.0041
71.
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Not in our library10.1016/0301-0082(96)00010-x
72.
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Not in our library10.1007/s00018-003-3084-x
73.
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Not in our library10.1196/annals.1372.004
74.
Schmidt RE Modert CW Yip HK Johnson EMJ Retrograde axonal transport of intravenously administered 125I-nerve growth factor in rats with streptozotocin-induced diabetesDiabetes1983 32654663
Not in our library10.2337/diab.32.7.654
75.
Faradji V Sotelo J Low serum levels of nerve growth factor in diabetic neuropathyActa Neurol Scand1990 81402406
Not in our library10.1111/j.1600-0404.1990.tb00984.x
76.
Fernyhough P Diemel LT Brewster WJ Tomlinson DR Altered neurotrophin mRNA levels in peripheral nerve and skeletal muscle of experimentally diabetic ratsJ Neurochem1995 6412311237
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77.
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78.
Nicol GD Vasko MR Unraveling the story of NGF-mediated sensitization of nociceptive sensory neurons: ON or OFF the Trks?Mol Interv2007 72641
Not in our library10.1124/mi.7.1.6
79.
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Not in our library10.1096/fj.01-0253hyp
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81.
Sango K Verdes JM Hikawa N Horie H Tanaka S Inoue S Sotelo JR Takenaka T Nerve growth factor (NGF) restores depletions of calcitonin gene-related peptide and substance P in sensory neurons from diabetic mice in vitroJ Neurol Sci1994 12615
Not in our library10.1016/0022-510x(94)90087-6
82.
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Not in our library10.1016/s0002-9343(99)00011-x
83.
Apfel SC Arezzo JC Brownlee M Federoff H Kessler JA Nerve growth factor administration protects against experimental diabetic sensory neuropathyBrain Res1994 634712
Not in our library10.1016/0006-8993(94)90252-6
84.
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85.
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Not in our library10.1002/ana.410360221
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Apfel SC Kessler JA Adornato BT Litchy WJ Sanders C Rask CA Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF study groupNeurology1998 51695702
Not in our library10.1212/wnl.51.3.695
87.
Apfel SC Nerve growth factor for the treatment of diabetic neuropathy: what went wrong, what went right, and what does the future hold?Int Rev Neurobiol2002 50393413
Not in our library10.1016/s0074-7742(02)50083-0
88.
Apfel SC Schwartz S Adornato BT Freeman R Biton V Rendell M Vinik A Giuliani M Stevens JC Barbano R Dyck PJ Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: a randomized controlled trial. rhNGF clinical investigator groupJAMA2000 28422152221
Not in our library10.1001/jama.284.17.2215
89.
Berger JR Nath A Remedies for HIV-associated peripheral neuropathyNeurology2000 5420372038
Not in our library10.1212/wnl.54.11.2037
90.
Peltier AC Russell JW Recent advances in drug-induced neuropathiesCurr Opin Neurol2002 15633638
Not in our library10.1097/00019052-200210000-00015
91.
Simpson DM Haidich AB Schifitto G Yiannoutsos CT Geraci AP McArthur JC Katzenstein DA Severity of HIV-associated neuropathy is associated with plasma HIV-1 RNA levelsAIDS2002 16407412
Not in our library10.1097/00002030-200202150-00012
92.
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Not in our library
93.
McArthur JC Yiannoutsos C Simpson DM Adornato BT Singer EJ Hollander H Marra C Rubin M Cohen BA Tucker T A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291 [see comments] [published erratum appears in Neurology 2000 Jul 13;55(1):162]Neurology2000 5410801088
Not in our library10.1212/wnl.54.5.1080
94.
Schifitto G Yiannoutsos C Simpson DM Adornato BT Singer EJ Hollander H Marra CM Rubin M Cohen BA Tucker T Long-term treatment with recombinant nerve growth factor for HIV-associated sensory neuropathyNeurology2001 5713131316
Not in our library10.1212/wnl.57.7.1313
95.
Alberts DS Noel JK Cisplatin-associated neurotoxicity: can it be prevented?Anticancer Drugs1995 6369383
Not in our library10.1097/00001813-199506000-00003
96.
Konings PN Makkink WK van Delft AM Ruigt GS Reversal by NGF of cytostatic drug-induced reduction of neurite outgrowth in rat dorsal root ganglia in vitroBrain Res1994 640195204
Not in our library10.1016/0006-8993(94)91873-2
97.
Apfel SC Arezzo JC Lipson L Kessler JA Nerve growth factor prevents experimental cisplatin neuropathyAnn Neurol1992 317680
Not in our library10.1002/ana.410310114
98.
Hayakawa K Sobue G Itoh T Mitsuma T Nerve growth factor prevents neurotoxic effects of cisplatin, vincristine and taxol, on adult rat sympathetic ganglion explants in vitroLife Sci1994 55519525
Not in our library10.1016/0024-3205(94)00744-6
99.
Schmidt Y Unger JW Bartke I Reiter R Effect of nerve growth factor on peptide neurons in dorsal root ganglia after taxol or cisplatin treatment and in diabetic (db/db) miceExp Neurol1995 1321623
Not in our library10.1016/0014-4886(95)90054-3
100.
Hayakawa K Itoh T Niwa H Mutoh T Sobue G NGF prevention of neurotoxicity induced by cisplatin, vincristine and taxol depends on toxicity of each drug and NGF treatment schedule: in vitro study of adult rat sympathetic ganglion explantsBrain Res1998 794313319
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101.
Aloe L Manni L Properzi F De Santis S Fiore M Evidence that nerve growth factor promotes the recovery of peripheral neuropathy induced in mice by cisplatin: behavioral, structural and biochemical analysisAuton Neurosci2000 868493
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Not in our library10.1093/annonc/mdh348
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Facer P Mann D Mathur R Pandya S Ladiwala U Singhal B Hongo J Sinicropi DV Terenghi G Anand P Do nerve growth factor-related mechanisms contribute to loss of cutaneous nociception in leprosy?Pain2000 85231238
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104.
Anand P Pandya S Ladiwala U Singhal B Sinicropi DV Williams-Chestnut RE Depletion of nerve growth factor in leprosyLancet1994 344129130
Not in our library10.1016/s0140-6736(94)91316-1
105.
Facer P Mathur R Pandya SS Ladiwala U Singhal BS Anand P Correlation of quantitative tests of nerve and target organ dysfunction with skin immunohistology in leprosyBrain1998 121Pt 1222392247
Not in our library10.1093/brain/121.12.2239
106.
Anand P Nerve growth factor regulates nociception in human health and diseaseBr J Anaesth1995 75201208
Not in our library10.1093/bja/75.2.201
107.
Fischer W Wictorin K Bjorklund A Williams LR Varon S Gage FH Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factorNature1987 3296568
Not in our library10.1038/329065a0
108.
Hefti F Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transectionsJ Neurosci1986 621552162
Not in our library10.1523/jneurosci.06-08-02155.1986
109.
Kromer LF Nerve growth factor treatment after brain injury prevents neuronal deathScience1987 235214216
Not in our library10.1126/science.3798108
110.
Tuszynski MH U HS Amaral DG Gage FH Nerve growth factor infusion in the primate brain reduces lesion-induced cholinergic neuronal degenerationJ Neurosci1990 1036043614
Not in our library10.1523/jneurosci.10-11-03604.1990
111.
Tuszynski MH Sang H Yoshida K Gage FH Recombinant human nerve growth factor infusions prevent cholinergic neuronal degeneration in the adult primate brainAnn Neurol1991 30625636
Not in our library10.1002/ana.410300502
112.
Rossner S Ueberham U Schliebs R Perez-Polo JR Bigl V p75 and TrkA receptor signaling independently regulate amyloid precursor protein mRNA expression, isoform composition, and protein secretion in PC12 cellsJ Neurochem1998 71757766
Not in our library10.1046/j.1471-4159.1998.71020757.x
113.
Rossner S Ueberham U Schliebs R Perez-Polo JR Bigl V The regulation of amyloid precursor protein metabolism by cholinergic mechanisms and neurotrophin receptor signalingProg Neurobiol1998 56541569
Not in our library10.1016/s0301-0082(98)00044-6
114.
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Not in our library10.1016/j.brainres.2011.12.059
115.
Nuydens R Dispersyn G de Jong M van den Kieboom G Borgers M Geerts H Aberrant tau phosphorylation and neurite retraction during NGF deprivation in PC12 cellsBiochem Biophys Res Commun1997 240687691
Not in our library10.1006/bbrc.1997.7721
116.
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Not in our library10.1016/j.jocn.2009.07.086
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Scott SA Mufson EJ Weingartner JA Skau KA Crutcher KA Nerve growth factor in Alzheimer's disease: increased levels throughout the brain coupled with declines in nucleus basalisJ Neurosci1995 1562136221
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118.
Pan W Banks WA Kastin AJ Permeability of the blood–brain barrier to neurotrophinsBrain Res1998 7888794
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119.
Olson L Nordberg A von Holst H Backman L Ebendal T Alafuzoff I Amberla K Hartvig P Herlitz A Lilja A Nerve growth factor affects 11C-nicotine binding, blood flow, EEG, and verbal episodic memory in an Alzheimer patient (case report)J Neural Transm Park Dis Dement Sect1992 47995
Not in our library10.1007/bf02257624
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Eriksdotter Jonhagen M Nordberg A Amberla K Backman L Ebendal T Meyerson B Olson L Seiger Shigeta M Theodorsson E Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer's diseaseDement Geriatr Cogn Disord1998 9246257
Not in our library10.1159/000017069
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Olson L Backlund EO Ebendal T Freedman R Hamberger B Hansson P Hoffer B Lindblom U Meyerson B Stromberg I Intraputaminal infusion of nerve growth factor to support adrenal medullary autografts in Parkinson’s disease. One-year follow-up of first clinical trialArch Neurol1991 48373381
Not in our library10.1001/archneur.1991.00530160037011
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Chiaretti A Antonelli A Genovese O Fernandez E Giuda D Mariotti P Riccardi R Intraventricular nerve growth factor infusion improves cerebral blood flow and stimulates doublecortin expression in two infants with hypoxic-ischemic brain injuryNeurol Res2008 30223228
Not in our library10.1179/016164107x247948
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Chiaretti A Genovese O Riccardi R Di Rocco C Di Giuda D Mariotti P Pulitano S Piastra M Polidori G Colafati GS Aloe L Intraventricular nerve growth factor infusion: a possible treatment for neurological deficits following hypoxic-ischemic brain injury in infantsNeurol Res2005 27741746
Not in our library10.1179/016164105x35611
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Chiaretti A Piastra M Polidori G Di Rocco C Caresta E Antonelli A Amendola T Aloe L Correlation between neurotrophic factor expression and outcome of children with severe traumatic brain injuryIntensive Care Med2003 2913291338
Not in our library10.1007/s00134-003-1852-6
125.
Date I Ohmoto T Neural transplantation and trophic factors in Parkinson's disease: special reference to chromaffin cell grafting, NGF support from pretransected peripheral nerve, and encapsulated dopamine-secreting cell graftingExp Neurol1996 137333344
Not in our library10.1006/exnr.1996.0034
126.
Olson L Backman L Ebendal T Eriksdotter-Jonhagen M Hoffer B Humpel C Freedman R Giacobini M Meyerson B Nordberg A Role of growth factors in degeneration and regeneration in the central nervous system; clinical experiences with NGF in Parkinson's and Alzheimer's diseasesJ Neurol1994 242S12S15
Not in our library10.1007/bf00939233
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Lindvall O Backlund EO Farde L Sedvall G Freedman R Hoffer B Nobin A Seiger A Olson L Transplantation in Parkinson's disease: two cases of adrenal medullary grafts to the putamenAnn Neurol1987 22457468
Not in our library10.1002/ana.410220403
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Backlund EO Granberg PO Hamberger B Knutsson E Martensson A Sedvall G Seiger A Olson L Transplantation of adrenal medullary tissue to striatum in parkinsonism. First clinical trialsJ Neurosurg1985 62169173
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Eriksdotter-Jonhagen M Linderoth B Lind G Aladellie L Almkvist O Andreasen N Blennow K Bogdanovic N Jelic V Kadir A Encapsulated cell biodelivery of nerve growth factor to the Basal forebrain in patients with Alzheimer's diseaseDement Geriatr Cogn Disord2012 331828
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Not in our library10.1177/1545968310395601

Cited by papers we hold 6

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Innovative Therapy for Alzheimer’s Disease-With Focus on Biodelivery of NGF · 2019
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Magnetic Targeting of Growth Factors Using Iron Oxide Nanoparticles · 2018
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The Eye As a Biomarker for Alzheimer's Disease · 2016
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Neurotrophins and Neuropathic Pain: Role in Pathobiology · 2015
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