1. Adeno-associated viral vector serotype 9–based gene therapy for Niemann-Pick disease type A
- Author
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Samaranch, Lluis, Pérez-Cañamás, Azucena, Soto-Huelin, Beatriz, Sudhakar, Vivek, Jurado-Arjona, Jerónimo, Hadaczek, Piotr, Ávila, Jesús, Bringas, John R, Casas, Josefina, Chen, Haifeng, He, Xingxuan, Schuchman, Edward H, Cheng, Seng H, Forsayeth, John, Bankiewicz, Krystof S, and Ledesma, María Dolores
- Subjects
Medical Biotechnology ,Biomedical and Clinical Sciences ,Gene Therapy ,Rare Diseases ,Biotechnology ,Brain Disorders ,Neurosciences ,Neurodegenerative ,Genetics ,Neurological ,Animals ,Brain ,Dependovirus ,Genetic Therapy ,Humans ,Inflammation ,Injections ,Liver ,Mice ,Knockout ,Motor Activity ,Niemann-Pick Disease ,Type A ,Primates ,Serogroup ,Sphingomyelin Phosphodiesterase ,Transgenes ,Biological Sciences ,Medical and Health Sciences ,Medical biotechnology ,Biomedical engineering - 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.
- Published
- 2019