Single Systemic Administration of a Gene Therapy Leading to Disease Treatment in Metachromatic LeukodystrophyArsaKnockout Mice

Metachromatic leukodystrophy (MLD) is a rare, inherited, demyelinating lysosomal storage disorder caused by mutations in the arylsulfatase-A gene (ARSA). In patients, levels of functional arylsulfatase-A enzyme (ARSA) are diminished and lead to deleterious accumulation of sulfatides. Herein, we demonstrate that intravenous (i.v). administration of HSC15/ARSArestored the endogenous murine biodistribution of the corresponding enzyme and overexpression ofARSAcorrected disease biomarkers and ameliorated motor deficits inArsaKO mice of either sex. In treatedArsaKO mice, when compared to i.v. administered AAV9/ARSA,significant increases in brain ARSA activity, transcript levels and vector genomes were observed with HSC15/ARSA.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 serum of healthy non-human primates (NHP) of either sex. Taken together, these findings support the use of i.v. delivery of HSC15/ARSA-mediated gene therapy for the treatment of MLD.SIGNIFICANCE STATEMENTHerein, we describe the method of gene therapy 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, biodistribution profile (with a focus on the CNS) with that of key clinically relevant biomarker.