Single Systemic Administration of a Gene Therapy Leading to Disease Treatment in Metachromatic Leukodystrophy Arsa Knock-Out 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 ARSA enzyme are diminished and lead to deleterious accumulation of sulfatides. Herein, we demonstrate that intravenous administration of HSC15/ARSA restored the endog-enous murine biodistribution of the corresponding enzyme, and overexpression of ARSA corrected disease biomarkers and ameliorated motor deficits in Arsa KO mice of either sex. In treated Arsa KO mice, when compared with intrave-nously 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 the serum of healthy nonhuman primates of either sex. Together, these findings support the use of intravenous delivery of HSC15/ARSA-mediated gene therapy for the treatment of MLD.

Automated summary

This study demonstrates that intravenous administration of HSC15/ARSA can restore the distribution of the corresponding enzyme in patients, and overexpression of ARSA can correct disease biomarkers and improve motor deficits. Compared with intravenously administered AAV9/ARSA, HSC15/ARSA leads to significant increases in brain ARSA activity, transcript levels, and vector genomes. Additionally, the study shows that HSC15/ARSA can cross the blood-nerve, blood-spinal, and blood-brain barriers, and circulating ARSA enzyme activity can be detected in the serum of healthy nonhuman primates.