Adeno-associated viral vector serotype 9–based gene therapy for Niemann-Pick disease type A

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Science Translational Medicine  21 Aug 2019:
Vol. 11, Issue 506, eaat3738
DOI: 10.1126/scitranslmed.aat3738

Safe and effective gene delivery

Niemann-Pick type A disease (NPD-A) is caused by loss-of-function mutations in the gene encoding for acid sphingomyelinase (ASM). Patients present mental retardation with prominent loss of early motor skills and cognitive decline and early death. Gene replacement therapy has been shown to be effective in other monogenic neurological disorders. Now, Samaranch et al. evaluated the safety and efficacy of adeno-associated viral vector serotype 9 (AAV9)–based gene therapy. AAV9-mediated delivery of human ASM in the cerebellomedullary cistern allowed widespread gene expression in the brain and spinal cord of nonhuman primates without signs of toxicity. The treatment prevented motor and memory impairment and increased survival in a mouse model of NPD-A.


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.

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