Identification of a novel fusion Iduronidase with improved activity in the cardiovascular system

Background: Lysosomal diseases are a group of over 70 rare, genetic diseases that commonly lead to enzyme deficiency and multi-systemic disorders. Currently, only 12 lysosomal diseases have approved treatments, and current therapies have difficulty reaching certain tissues that are major contributors to morbidity and mortality, such as the central nervous system (CNS) and cardiac valves. Therefore, the objective of this study was to improve the delivery of therapeutic enzymes, via gene therapy, to targeted tissues in lysosomal diseases. The lysosomal disease mucopolysaccharidosis type I (MPS I) was selected as the disease model. In MPS I, mutations in the IDUA gene cause a deficiency of the α-L-iduronidase (IDUA) enzyme, leading to disease pathology in tissues throughout the body, including the CNS and cardiac valves. Current therapies have been unable to prevent neurodevelopmental deficits and cardiac valvular disease in patients with MPS I. Methods: MPS I mice were hydrodynamically injected with plasmids containing either a codon-optimized cDNA encoding the IDUA protein or one of four modified IDUAs. Two modified IDUAs contained a ligand for the CB1 receptor, which is a highly expressed receptor in the CNS. Iduronidase activity levels were measured in the tissues and plasma using an enzyme activity assay. Results: The modified IDUAs did not appear to have improved activity levels in the brain compared with the unmodified IDUA. However, one modified IDUA exhibited higher activity levels than the unmodified IDUA in the heart (p=0.0211). This modified iduronidase (LT-IDUA) contained a sequence for a six amino acid peptide termed LT. LT-IDUA was further characterized using a noncompartmental pharmacokinetic approach that directly analyzed enzyme activity levels after gene delivery. LT-IDUA had a 2-fold higher area under the curve (AUC) than the unmodified IDUA (p=0.0034) when AUC was estimated using enzyme activity levels in the plasma. Conclusion: The addition of a six amino acid peptide improved iduronidase’s activity levels in the heart and plasma. The short length of this LT peptide facilitates its use as fusion enzymes encoded as gene therapy or administered as enzyme replacement therapy. More broadly, the LT peptide may aid in developing therapies for numerous lysosomal diseases.

Abstract licence: CC BY-NC-ND

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