ArticleHuman gene therapy2016
Novel Vector Design and Hexosaminidase Variant Enabling Self-Complementary Adeno-Associated Virus for the Treatment of Tay-Sachs Disease.
Article in Human gene therapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 44 citations in OpenAlex.
- Design and initial characterization of a novel mini-promoter for gene therapies targeting the central nervous system.Molecular therapy. Advances · 2026Article
- Improved AAV9-based gene therapy design forMolecular therapy. Methods & clinical development · 2025Article
- Age-sensitive response of systemic AAV-mediated gene therapy in a newly characterized feline model of mucolipidosis II.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- In vivo applications and toxicities of AAV-based gene therapies in rare diseases.Orphanet journal of rare diseases · 2025Review
- Intracerebroventricular administration of a modified hexosaminidase ameliorates late-stage neurodegeneration in a GM2 mouse model.PloS one · 2025Article
- Treating late-onset Tay Sachs disease: Brain delivery with a dual trojan horse protein.Molecular therapy. Methods & clinical development · 2024Article
- Intrathecal delivery of a bicistronic AAV9 vector expressing β-hexosaminidase A corrects Sandhoff disease in a murine model: A dosage study.Molecular therapy. Methods & clinical development · 2024Article
- Increasing β-hexosaminidase A activity using genetically modified mesenchymal stem cells.Neural regeneration research · 2024Article
- Life-Limiting Peripheral Organ Dysfunction in Feline Sandhoff Disease Emerges after Effective CNS Gene Therapy.Annals of neurology · 2023Article
- Paving a way to treat spastic paraplegia 50.The Journal of clinical investigation · 2023Article
- Intrathecal AAV9/AP4M1 gene therapy for hereditary spastic paraplegia 50 shows safety and efficacy in preclinical studies.The Journal of clinical investigation · 2023Article
- Advancement in CRISPR/Cas9 Technology to Better Understand and Treat Neurological Disorders.Cellular and molecular neurobiology · 2023Review
- spJournal of enzyme inhibition and medicinal chemistry · 2022Article
- The GM2 gangliosidoses: Unlocking the mysteries of pathogenesis and treatment.Neuroscience letters · 2021Article
- Investigating Immune Responses to the scAAV9-International journal of molecular sciences · 2021Article
- Gene Therapy for Lysosomal Storage Disorders: Ongoing Studies and Clinical Development.Biomolecules · 2021Review
- Targeting Gys1 with AAV-SaCas9 Decreases Pathogenic Polyglucosan Bodies and Neuroinflammation in Adult Polyglucosan Body and Lafora Disease Mouse Models.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Article
- Letter to the Editor.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- Adeno-Associated Virus Capsid-Promoter Interactions in the Brain Translate from Rat to the Nonhuman Primate.Human gene therapy · 2020Article
- Dual Purpose Vectors for Rare Neurological Diseases.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
GM2 gangliosidosis is a family of three genetic neurodegenerative disorders caused by the accumulation of GM2 ganglioside (GM2) in neuronal tissue. Two of these are due to the deficiency of the heterodimeric (α-β), "A" isoenzyme of lysosomal β-hexosaminidase (HexA). Mutations in the α-subunit (encoded by HEXA) lead to Tay-Sachs disease (TSD), whereas mutations in the β-subunit (encoded by HEXB) lead to Sandhoff disease (SD). The third form results from a deficiency of the GM2 activator protein (GM2AP), a substrate-specific cofactor for HexA. In their infantile, acute forms, these diseases rapidly progress with mental and psychomotor deterioration resulting in death by approximately 4 years of age. After gene transfer that overexpresses one of the deficient subunits, the amount of HexA heterodimer formed would empirically be limited by the availability of the other endogenous Hex subunit. The present study used a new variant of the human HexA α-subunit, μ, incorporating critical sequences from the β-subunit that produce a stable homodimer (HexM) and promote functional interactions with the GM2AP- GM2 complex. We report the design of a compact adeno-associated viral (AAV) genome using a synthetic promoter-intron combination to allow self-complementary (sc) packaging of the HEXM gene. Also, a previously published capsid mutant, AAV9.47, was used to deliver the gene to brain and spinal cord while having restricted biodistribution to the liver. The novel capsid and cassette design combination was characterized in vivo in TSD mice for its ability to efficiently transduce cells in the central nervous system when delivered intravenously in both adult and neonatal mice. This study demonstrates that the modified HexM is capable of degrading long-standing GM2 storage in mice, and it further demonstrates the potential of this novel scAAV vector design to facilitate widespread distribution of the HEXM gene or potentially other similar-sized genes to the nervous system.
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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.