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ResearchIn-Press PreviewGeneticsNeuroscience Open Access | 10.1172/JCI185001

Cross-species efficacy of AAV-mediated ARSA replacement for Metachromatic Leukodystrophy

Shyam Ramachandran,1 Jeffery Ardinger,1 Jie Bu,1 MiAngela Ramos,1 Lilu Guo,2 Dhiman Ghosh,2 Mahmud Hossain,2 Shih-Ching Chou,1 Yao Chen,2 Erik Wischhof,1 Swathi Ayloo,1 Roger Trullo,4 Yuxia Luo,1 Jessica M. Hogestyn,1 Daniel M. DuBreuil,1 Emily Crosier,1 Johanna G. Flyer-Adams,1 Amy M. Richards,1 Michael Tsabar,2 Giorgio Gaglia,2 Shelley Nass,1 Bindu Nambiar,1 Denise Woodcock,1 Catherine O'Riordan,1 Qi Tang,4 Bradford Elmer,1 Bailin Zhang,2 Martin Goulet,1 and Christian Mueller1

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Published June 19, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI185001.
Copyright © 2025, Ramachandran et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 19, 2025 - Version history
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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 an engineered 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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