Cross-species efficacy of AAV-mediated ARSA replacement for metachromatic leukodystrophy

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 virus (AAV) vectors have been promising but hampered by limited brain biodistribution. We report the development of an engineered capsid, AAV.GMU01, demonstrating superior biodistribution and transgene expression in the central nervous system of nonhuman 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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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-06-19
DOI
https://doi.org/10.1172/jci185001
Citations
4
Primary Topic
Lysosomal Storage Disorders Research
Type
article
Field-Weighted Citation Impact
4.66

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article

Cross-species efficacy of AAV-mediated ARSA replacement for metachromatic leukodystrophy

Jeffery Ardinger, Giorgio Gaglia, Johanna G. Flyer-Adams, Yongde Luo et al.
4 citations
Journal of Clinical Investigation
Lysosomal Storage Disorders Research
4.66
article

Cross-species efficacy of AAV-mediated ARSA replacement for metachromatic leukodystrophy

Jeffery Ardinger, Giorgio Gaglia, Johanna G. Flyer-Adams, Yongde Luo, Debabrata Ghosh, Roger Trullo, Catherine R. O’Riordan, Shelley Nass, Denise Woodcock, Bindu Nambiar, Qi Tang, Shyam Ramachandran, Mahmud Hossain, Bradford Elmer, Swathi Ayloo, Amy M. Richards, Jie Bu, Chen Yao, Bailin Zhang, Christian Mueller, Lilu Guo, M. Isabel Alcalá Ramos, Jessica M. Hogestyn, Martin Goulet, Shelley N. Chou, Daniel M. DuBreuil, Emily Crosier, Michael Tsabar, Erik Wischhof
article en
4 citations

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 virus (AAV) vectors have been promising but hampered by limited brain biodistribution. We report the development of an engineered capsid, AAV.GMU01, demonstrating superior biodistribution and transgene expression in the central nervous system of nonhuman 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.

Journal of Clinical InvestigationVol. 135(16)
AVEO Oncology (United States) (US), Sanofi (United States) (US), Precision for Medicine (United States) (US), Center for Genomic Science (IT)
Sanofi, University of Miami, National Institutes of Health
Openalex Percentile: Top 5%
Lysosomal Storage Disorders Research
4.66
DOIOpen Access PDFOpenAlex
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