Intracerebral Gene Therapy Using AAVrh.10-hARSA Recombinant Vector to Treat Patients with Early-Onset Forms of Metachromatic Leukodystrophy: Preclinical Feasibility and Safety Assessments in Nonhuman Primates

Michel Zerah, Françoise Piguet, Marie Anne Colle, Sylvie Raoul, Jack Yves Deschamps, Johan Deniaud, Benoit Gautier, Frédérique Toulgoat, Ivan Bieche, Ingrid Laurendeau, Dolan Sondhi, Mark M. Souweidane, Nathalie Cartier-Lacave, Philippe Moullier, Ronald Crystal, Thomas Roujeau, Caroline Sevin, Patrick Aubourg

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Abstract

No treatment is available for early-onset forms of metachromatic leukodystrophy (MLD), a lysosomal storage disease caused by autosomal recessive defect in arylsulfatase A (ARSA) gene causing severe demyelination in central and peripheral nervous systems. We have developed a gene therapy approach, based on intracerebral administration of AAVrh.10-hARSA vector, coding for human ARSA enzyme. We have previously demonstrated potency of this approach in MLD mice lacking ARSA expression. We describe herein the preclinical efficacy, safety, and biodistribution profile of intracerebral administration of AAVrh.10-hARSA to nonhuman primates (NHPs). NHPs received either the dose planned for patients adjusted to the brain volume ratio between child and NHP (1×dose, 1.1×1011 vg/hemisphere, unilateral or bilateral injection) or 5-fold this dose (5×dose, 5.5×1011 vg/hemisphere, bilateral injection). NHPs were subjected to clinical, biological, and brain imaging observations and were euthanized 7 or 90 days after injection. There was no toxicity based on clinical and biological parameters, nor treatment-related histological findings in peripheral organs. A neuroinflammatory process correlating with brain MRI T2 hypersignals was observed in the brain 90 days after administration of the 5×dose, but was absent or minimal after administration of the 1×dose. Antibody response to AAVrh.10 and hARSA was detected, without correlation with brain lesions. After injection of the 1×dose, AAVrh.10-hARSA vector was detected in a large part of the injected hemisphere, while ARSA activity exceeded the normal endogenous activity level by 14-31%. Consistently with other reports, vector genome was detected in off-target organs such as liver, spleen, lymph nodes, or blood, but not in gonads. Importantly, AAVrh.10-hARSA vector was no longer detectable in urine at day 7. Our data demonstrate requisite safe and effective profile for intracerebral AAVrh.10-hARSA delivery in NHPs, supporting its clinical use in children affected with MLD.

Original languageEnglish
Pages (from-to)113-124
Number of pages12
JournalHuman Gene Therapy Clinical Development
Volume26
Issue number2
DOIs
Publication statusPublished - 1 Jun 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Zerah, M., Piguet, F., Colle, M. A., Raoul, S., Deschamps, J. Y., Deniaud, J., Gautier, B., Toulgoat, F., Bieche, I., Laurendeau, I., Sondhi, D., Souweidane, M. M., Cartier-Lacave, N., Moullier, P., Crystal, R., Roujeau, T., Sevin, C., & Aubourg, P. (2015). Intracerebral Gene Therapy Using AAVrh.10-hARSA Recombinant Vector to Treat Patients with Early-Onset Forms of Metachromatic Leukodystrophy: Preclinical Feasibility and Safety Assessments in Nonhuman Primates. Human Gene Therapy Clinical Development, 26(2), 113-124. https://doi.org/10.1089/humc.2014.139