ArticleScience translational medicine2019
Adeno-associated viral vector serotype 9-based gene therapy for Niemann-Pick disease type A.
Article in Science translational medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 51 citations in OpenAlex.
- Targeting CD44 reverses sphingomyelin-induced oligodendrocyte maturation arrest in acid sphingomyelinase deficiency.EMBO molecular medicine · 2026Article
- Ceramides as Biomarkers and Pharmacological Targets in Heart Failure Pathophysiology.Biomolecules · 2026Review
- Interferon-stimulated gene GALNT2 restricts respiratory virus infections.Nature microbiology · 2026Article
- Review
- Retention of lysosomal acid sphingomyelinase protects from Niemann-Pick Disease.Neurobiology of disease · 2025Article
- The impact of sphingomyelin on the pathophysiology and treatment response to olipudase alfa in acid sphingomyelinase deficiency.Genetics in medicine open · 2024Review
- Gene Therapy of Sphingolipid Metabolic Disorders.International journal of molecular sciences · 2023Review
- Recombinant adeno-associated virus serotype 9 AAV-RABVG expressing a Rabies Virus G protein confers long-lasting immune responses in mice and non-human primates.Emerging microbes & infections · 2022Article
- AAV-mediated gene therapy produces fertile offspring in the Lhcgr-deficient mouse model of Leydig cell failure.Cell reports. Medicine · 2022Article
- Transduction characteristics of alternative adeno-associated virus serotypes in the cat brain by intracisternal delivery.Molecular therapy. Methods & clinical development · 2022Article
- Review
- Breast carcinoma-amplified sequence 2 regulates adult neurogenesis via β-catenin.Stem cell research & therapy · 2022Article
- Secreted acid sphingomyelinase as a potential gene therapy for limb girdle muscular dystrophy 2B.The Journal of clinical investigation · 2022Article
- Gene therapy using an ortholog of human fragile X mental retardation protein partially rescues behavioral abnormalities and EEG activity.Molecular therapy. Methods & clinical development · 2021Article
- Gene Therapy in a Mouse Model of Niemann-Pick Disease Type C1.Human gene therapy · 2021Article
- Preexposure and Postexposure Prophylaxis of Rabies With Adeno-Associated Virus Expressing Virus-Neutralizing Antibody in Rodent Models.Frontiers in microbiology · 2021Article
- Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord.Frontiers in molecular neuroscience · 2021Review
- Design and Validation of a Multi-Point Injection Technology for MR-Guided Convection Enhanced Delivery in the Brain.Frontiers in medical technology · 2021Article
- Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease.International journal of molecular sciences · 2020Review
- AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Review
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 3 countries.
Funding
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.
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