ArticleHuman gene therapy2012
Safety study of adeno-associated virus serotype 2-mediated human acid sphingomyelinase expression in the nonhuman primate brain.
Article in Human gene therapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
19 citing papers in PubMed, 38 citations in OpenAlex.
- Review
- Retention of lysosomal acid sphingomyelinase protects from Niemann-Pick Disease.Neurobiology of disease · 2025Article
- A Spatial Interpolation Approach to Assign Magnetic Resonance Imaging-Derived Material Properties for Finite Element Models of Adeno-Associated Virus Infusion Into a Recurrent Brain Tumor.Journal of biomechanical engineering · 2024Article
- State-of-the-art therapies for fragile X syndrome.Developmental medicine and child neurology · 2024Review
- Seven-year follow-up of durability and safety of AAV CNS gene therapy for a lysosomal storage disorder in a large animal.Molecular therapy. Methods & clinical development · 2021Article
- Sphingolipid lysosomal storage diseases: from bench to bedside.Lipids in health and disease · 2021Review
- CERTAlzheimer's research & therapy · 2021Article
- Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord.Frontiers in molecular neuroscience · 2021Review
- Fetal Gene Therapy Using a Single Injection of Recombinant AAV9 Rescued SMA Phenotype in Mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2019Article
- Adeno-associated viral vector serotype 9-based gene therapy for Niemann-Pick disease type A.Science translational medicine · 2019Article
- Direct Intracranial Injection of AAVrh8 Encoding Monkey β-N-Acetylhexosaminidase Causes Neurotoxicity in the Primate Brain.Human gene therapy · 2017Article
- Pervasive supply of therapeutic lysosomal enzymes in the CNS of normal and Krabbe-affected non-human primates by intracerebral lentiviral gene therapy.EMBO molecular medicine · 2016Article
- Gene Therapy for the Treatment of Neurological Disorders: Metabolic Disorders.Methods in molecular biology (Clifton, N.J.) · 2016Review
- Noninvasive, neuron-specific gene therapy can be facilitated by focused ultrasound and recombinant adeno-associated virus.Gene therapy · 2015Article
- Gene therapy for the nervous system: challenges and new strategies.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2014Review
- Global CNS transduction of adult mice by intravenously delivered rAAVrh.8 and rAAVrh.10 and nonhuman primates by rAAVrh.10.Molecular therapy : the journal of the American Society of Gene Therapy · 2014Article
- Fetal Brain-directed AAV Gene Therapy Results in Rapid, Robust, and Persistent Transduction of Mouse Choroid Plexus Epithelia.Molecular therapy. Nucleic acids · 2013Article
- Adenoviral and adeno-associated viral vectors-mediated neuronal gene transfer to cardiovascular control regions of the rat brain.International journal of medical sciences · 2013Article
- Article
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
Abstract
Niemann-Pick disease is a lysosomal storage disorder resulting from inherited deficiency in acid sphingomyelinase (ASM). Use of adeno-associated virus serotype 2 (AAV2) to deliver human acid sphingomyelinase (hASM) is currently being explored as a means to treat the devastating neurological features of NPD, which are refractory to traditional enzyme replacement therapy. In this study, we evaluated the long-term efficacy and safety of AAV2-hASM after direct infusion into the CNS of nonhuman primates. First, we confirmed the efficacy of AAV2-hASM in naive rats, which exhibited increased ASM expression and enzyme activity after infusion, without evidence of local or systemic toxicity. Next, the model was adapted to naive nonhuman primates (NHPs) with various doses of AAV2-hASM or saline delivered into the brainstem and both thalami. Strikingly, NHPs that received a high dose of AAV2-hASM displayed significant motor deficits that were not seen in low-dose animals in both the short-term (3-month) and long-term (9-month) treatment groups. In treated NHPs, ASM expression and activity were elevated with associated alterations in the sphingolipidomic profile in brain regions transduced with AAV2-hASM. Initial histological analysis indicated marked inflammatory reactions, and immunohistochemical analysis confirmed a robust inflammatory response. Importantly, pronounced upregulation of the chemokine CCL5, a target of ASM-mediated inflammatory signaling, was detected that correlated with the inflammatory response, providing a possible mechanism for hASM-associated toxicity. This study defines dose-dependent and dose-independent toxicities of AAV2-hASM in the naive primate brain, and reveals potential challenges in the design of a clinical trial.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.