title: 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.
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 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.
authors.affiliation: 1 Inserm U986, 94275 Le Kremlin Bicêtre , France .|2 Pediatric Neurosurgery, Necker Children's Hospital , 75014 Paris, France .
authors.forename: Michel
authors.initials: M
authors.lastname: Zerah
authors.affiliation: 1 Inserm U986, 94275 Le Kremlin Bicêtre , France .
authors.forename: Françoise
authors.initials: F
authors.lastname: Piguet
authors.affiliation: 3 INRA UMR U703 , 44000 Nantes, France .|4 Food Science and Engineering Oniris, Nantes-Atlantic College of Veterinary Medicine , 44000 Nantes, France .
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Colle
authors.affiliation: 5 Service de Neurochirurgie, CHU Nord , 44000 Nantes, France .
authors.forename: Sylvie
authors.initials: S
authors.lastname: Raoul
authors.affiliation: 3 INRA UMR U703 , 44000 Nantes, France .|4 Food Science and Engineering Oniris, Nantes-Atlantic College of Veterinary Medicine , 44000 Nantes, France .
authors.forename: Jack-Yves
authors.initials: JY
authors.lastname: Deschamps
authors.affiliation: 3 INRA UMR U703 , 44000 Nantes, France .
authors.forename: Johan
authors.initials: J
authors.lastname: Deniaud
authors.affiliation: 1 Inserm U986, 94275 Le Kremlin Bicêtre , France .
authors.forename: Benoit
authors.initials: B
authors.lastname: Gautier
authors.affiliation: 6 Neuroradiologie Diagnostique et Interventionnelle, Hôpital Laennec, CHU de Nantes , 44000 Nantes, France .
authors.forename: Frédérique
authors.initials: F
authors.lastname: Toulgoat
authors.affiliation: 7 Faculté des Sciences Pharmaceutiques et Biologiques , 75005 Paris, France .
authors.forename: Ivan
authors.initials: I
authors.lastname: Bieche
authors.affiliation: 7 Faculté des Sciences Pharmaceutiques et Biologiques , 75005 Paris, France .
authors.forename: Ingrid
authors.initials: I
authors.lastname: Laurendeau
authors.affiliation: 8 Department of Genetic Medicine, Weill-Cornell Medical College , New York, NY 10065.
authors.forename: Dolan
authors.initials: D
authors.lastname: Sondhi
authors.affiliation: 9 Neurological Surgery and Pediatrics, Weill-Cornell Medical College , New York, NY 10065.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Souweidane
authors.affiliation: 1 Inserm U986, 94275 Le Kremlin Bicêtre , France .
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cartier-Lacave
authors.affiliation: 10 Atlantic Gene Therapies, INSERM UMR 1089 , 44000 Nantes, France .
authors.forename: Philippe
authors.initials: P
authors.lastname: Moullier
authors.affiliation: 8 Department of Genetic Medicine, Weill-Cornell Medical College , New York, NY 10065.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
authors.affiliation: 11 Neurosurgery, Hôpitaux de Montpellier , 34000 Montpellier, France .
authors.forename: Thomas
authors.initials: T
authors.lastname: Roujeau
authors.affiliation: 1 Inserm U986, 94275 Le Kremlin Bicêtre , France .|12 Neuropediatrics Unit, Bicêtre Hospital , 94275 Le Kremlin Bicêtre, France .
authors.forename: Caroline
authors.initials: C
authors.lastname: Sevin
authors.affiliation: 1 Inserm U986, 94275 Le Kremlin Bicêtre , France .|12 Neuropediatrics Unit, Bicêtre Hospital , 94275 Le Kremlin Bicêtre, France .
authors.forename: Patrick
authors.initials: P
authors.lastname: Aubourg
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002553:Cerebroside-Sulfatase / Q000235:genetics* / Q000378:metabolism; D002648:Child; D000229:Dependovirus / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007966:Leukodystrophy, Metachromatic / Q000628:therapy*; D008252:Macaca fascicularis; D008297:Male
chemical_list: D002553:Cerebroside-Sulfatase