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
Michel ZerahP Aubourg

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, 1.1×10(11) vg/hemisphere, unilateral or bilateral injection) or 5-fold this dose (5×dose, 5.5×10(11) 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 ...Continue Reading

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Citations

Nov 26, 2015·Human Molecular Genetics·Alessandra Biffi
Dec 30, 2015·Human Gene Therapy·Florie BorelChristian Mueller
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Jan 8, 2020·Molecular Therapy. Methods & Clinical Development·Michaël HocquemillerRalph Laufer
Sep 23, 2021·Journal of Virology·Mario MietzschMavis Agbandje-McKenna

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Methods Mentioned

BETA
PCR
ELISA
biopsy

Clinical Trials Mentioned

NCT01560182
NCT01510028
NCT01801709

Software Mentioned

Osirix Imaging

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