AAV-mediated ARSA replacement for the treatment of Metachromatic Leukodystrophy
Ramachandran, S.; Ardinger, J.; Bu, J.; Ramos, M.; Guo, L.; Ghosh, D.; Hossain, M.; Chou, S.-C.; Chen, Y.; Wischof, E.; Ayloo, S.; Trullo, R.; Luo, Y.; Hogestyn, J.; DuBreuil, D.; Crosier, E.; Adams, J.; Richards, A.; Tsabar, M.; Gaglia, G.; Nass, S.; Nambiar, B.; Woodcock, D.; O'Riordan, C.; Tang, Q.; Elmer, B.; Zhang, B.; Goulet, M.; Mueller, C.
Show abstract
Metachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative disorder caused by mutations in the arylsulfatase A (ARSA) gene, resulting in lower sulfatase activity and the toxic accumulation of sulfatides in the central and peripheral nervous system. Children account for 70% of cases and become progressively disabled with death occurring within 10 years of disease onset. Gene therapy approaches to restore ARSA expression via adeno-associated viral vectors (AAV) have been promising but hampered by limited brain biodistribution. We report the development of a novel capsid AAV.GMU01, demonstrating superior biodistribution and transgene expression in the central nervous system of non-human primates (NHPs). Next, we show that AAV.GMU01-ARSA treated MLD mice exhibit persistent, normal levels of sulfatase activity and a concomitant reduction in toxic sulfatides. Treated mice also show a reduction in MLD-associated pathology and auditory dysfunction. Lastly, we demonstrate that treatment with AAV.GMU01-ARSA in NHPs is well-tolerated and results in potentially therapeutic ARSA expression in the brain. In summary, we propose AAV.GMU01-ARSA mediated gene replacement as a clinically viable approach to achieve broad and therapeutic levels of ARSA.
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