Single Systemic Administration of a Gene Therapy Leading to Disease Treatment in Metachromatic Leukodystrophy Arsa Knock-Out Mice

• Published in: The Journal of neuroscience Vol. 43; no. 19; pp. 3567 - 3581
• Main Authors: St Martin, Thia, Seabrook, Tania A, Gall, Katherine, Newman, Jenn, Avila, Nancy, Hayes, April, Kivaa, Monicah, Lotterhand, Jason, Mercaldi, Michael, Patel, Kruti, Rivas, Israel J, Woodcock, Stephen, Wright, Teresa L, Seymour, Albert B, Francone, Omar L, Gingras, Jacinthe
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 10.05.2023
• Subjects: Administration, Intravenous; Animals; Arylsulfatase; Arylsulfatases - genetics; Biomarkers; Biomarkers - analysis; Blood circulation; Blood-Brain Barrier; Brain - enzymology; Demyelination; Dependovirus - genetics; Disease Models, Animal; Durability; Enzymatic activity; Enzyme activity; Enzymes; Female; Gene therapy; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Genomes; Humans; Intravenous administration; Leukodystrophy; Leukodystrophy, Metachromatic - genetics; Leukodystrophy, Metachromatic - physiopathology; Leukodystrophy, Metachromatic - therapy; Macaca fascicularis; Male; Medical treatment; Mice; Mice, Knockout; Motor Disorders - genetics; Motor Disorders - therapy; Sex; metachromatic leukodystrophy; motor deficit; translation; gene therapy; biomarker; AAVHSC
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1829-22.2023

Metachromatic leukodystrophy (MLD) is a rare, inherited, demyelinating lysosomal storage disorder caused by mutations in the arylsulfatase-A gene ( ). In patients, levels of functional ARSA enzyme are diminished and lead to deleterious accumulation of sulfatides. Herein, we demonstrate that intravenous administration of HSC15/ restored the endogenous murine biodistribution of the corresponding enzyme, and overexpression of corrected disease biomarkers and ameliorated motor deficits in KO mice of either sex. In treated KO mice, when compared with intravenously administered AAV9/ significant increases in brain ARSA activity, transcript levels, and vector genomes were observed with HSC15/ Durability of transgene expression was established in neonate and adult mice out to 12 and 52 weeks, respectively. Levels and correlation between changes in biomarkers and ARSA activity required to achieve functional motor benefit was also defined. Finally, we demonstrated blood-nerve, blood-spinal and blood-brain barrier crossing as well as the presence of circulating ARSA enzyme activity in the serum of healthy nonhuman primates of either sex. Together, these findings support the use of intravenous delivery of HSC15/ -mediated gene therapy for the treatment of MLD. Herein, we describe the method of gene therapy adeno-associated virus (AAV) capsid and route of administration selection leading to an efficacious gene therapy in a mouse model of metachromatic leukodystrophy. We demonstrate the therapeutic outcome of a new naturally derived clade F AAV capsid (AAVHSC15) in a disease model and the importance of triangulating multiple end points to increase the translation into higher species via ARSA enzyme activity and biodistribution profile (with a focus on the CNS) with that of a key clinically relevant biomarker.