1. Adeno-associated viral vector serotype 9-based gene therapy for Niemann-Pick disease type A.
- Author
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Samaranch L, Pérez-Cañamás A, Soto-Huelin B, Sudhakar V, Jurado-Arjona J, Hadaczek P, Ávila J, Bringas JR, Casas J, Chen H, He X, Schuchman EH, Cheng SH, Forsayeth J, Bankiewicz KS, and Ledesma MD
- Subjects
- Animals, Brain metabolism, Brain pathology, Humans, Inflammation pathology, Injections, Liver pathology, Mice, Knockout, Motor Activity, Primates, Sphingomyelin Phosphodiesterase administration & dosage, Sphingomyelin Phosphodiesterase blood, Sphingomyelin Phosphodiesterase genetics, Transgenes, Dependovirus metabolism, Genetic Therapy, Niemann-Pick Disease, Type A genetics, Niemann-Pick Disease, Type A therapy, Serogroup
- Abstract
Niemann-Pick disease type A (NPD-A) is a lysosomal storage disorder characterized by neurodegeneration and early death. It is caused by loss-of-function mutations in the gene encoding for acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin into ceramide. Here, we evaluated the safety of cerebellomedullary (CM) cistern injection of adeno-associated viral vector serotype 9 encoding human ASM (AAV9-hASM) in nonhuman primates (NHP). We also evaluated its therapeutic benefit in a mouse model of the disease (ASM-KO mice). We found that CM injection in NHP resulted in widespread transgene expression within brain and spinal cord cells without signs of toxicity. CM injection in the ASM-KO mouse model resulted in hASM expression in cerebrospinal fluid and in different brain areas without triggering an inflammatory response. In contrast, direct cerebellar injection of AAV9-hASM triggered immune response. We also identified a minimally effective therapeutic dose for CM injection of AAV9-hASM in mice. Two months after administration, the treatment prevented motor and memory impairment, sphingomyelin (SM) accumulation, lysosomal enlargement, and neuronal death in ASM-KO mice. ASM activity was also detected in plasma from AAV9-hASM CM-injected ASM-KO mice, along with reduced SM amount and decreased inflammation in the liver. Our results support CM injection for future AAV9-based clinical trials in NPD-A as well as other lysosomal storage brain disorders., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2019
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