ArticleHuman gene therapy. Clinical development2015
A GLP-Compliant Toxicology and Biodistribution Study: Systemic Delivery of an rAAV9 Vector for the Treatment of Mucopolysaccharidosis IIIB.
Article in Human gene therapy. Clinical development, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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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.
The trial behind it
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
14 citing papers in PubMed, 27 citations in OpenAlex.
- 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
- Safety and Tolerability of the Adeno-Associated Virus Vector, AAV6.2FF, Expressing a Monoclonal Antibody in Murine and Ovine Animal Models.Biomedicines · 2021Article
- Targeting the Root Cause of Mucopolysaccharidosis IIIA with a New scAAV9 Gene Replacement Vector.Molecular therapy. Methods & clinical development · 2020Article
- Challenging behavior in mucopolysaccharidoses types I-III and day-to-day coping strategies: a cross sectional explorative study.Orphanet journal of rare diseases · 2020Review
- A Cure for Sanfilippo Syndrome? A Summary of Current Therapeutic Approaches and their Promise.Medical research archives · 2020Article
- An Engineered Galactosylceramidase Construct Improves AAV Gene Therapy for Krabbe Disease in Twitcher Mice.Human gene therapy · 2019Article
- Threshold for Pre-existing Antibody Levels Limiting Transduction Efficiency of Systemic rAAV9 Gene Delivery: Relevance for Translation.Molecular therapy. Methods & clinical development · 2019Article
- An Isolated Limb Infusion Method Allows for Broad Distribution of rAAVrh74.MCK.Molecular therapy. Methods & clinical development · 2018Article
- Targeting Root Cause by Systemic scAAV9-hMolecular therapy. Methods & clinical development · 2018Article
- Gene therapy for Mucopolysaccharidoses.Molecular genetics and metabolism · 2018Review
- How close are we to therapies for Sanfilippo disease?Metabolic brain disease · 2018Review
- Adeno-associated viral gene therapy for mucopolysaccharidoses exhibiting neurodegeneration.Journal of molecular medicine (Berlin, Germany) · 2017Review
- Direct Intracranial Injection of AAVrh8 Encoding Monkey β-N-Acetylhexosaminidase Causes Neurotoxicity in the Primate Brain.Human gene therapy · 2017Article
- Superior In vivo Transduction of Human Hepatocytes Using Engineered AAV3 Capsid.Molecular therapy : the journal of the American Society of Gene Therapy · 2016Article
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
Abstract
No treatment is currently available for mucopolysaccharidosis (MPS) IIIB, a neuropathic lysosomal storage disease due to defect in α-N-acetylglucosaminidase (NAGLU). In preparation for a clinical trial, we performed an IND-enabling GLP-toxicology study to assess systemic rAAV9-CMV-hNAGLU gene delivery in WT C57BL/6 mice at 1 × 10(14) vg/kg and 2 × 10(14) vg/kg (n = 30/group, M:F = 1:1), and non-GLP testing in MPS IIIB mice at 2 × 10(14) vg/kg. Importantly, no adverse clinical signs or chronic toxicity were observed through the 6 month study duration. The rAAV9-mediated rNAGLU expression was rapid and persistent in virtually all tested CNS and somatic tissues. However, acute liver toxicity occurred in 33% (5/15) WT males in the 2 × 10(14) vg/kg cohort, which was dose-dependent, sex-associated, and genotype-specific, likely due to hepatic rNAGLU overexpression. Interestingly, a significant dose response was observed only in the brain and spinal cord, whereas in the liver at 24 weeks postinfection (pi), NAGLU activity was reduced to endogenous levels in the high dose cohort but remained at supranormal levels in the low dose group. The possibility of rAAV9 germline transmission appears to be minimal. The vector delivery resulted in transient T-cell responses and characteristic acute antibody responses to both AAV9 and rNAGLU in all rAAV9-treated animals, with no detectable impacts on tissue transgene expression. This study demonstrates a generally safe and effective profile, and may have identified the upper dosing limit of rAAV9-CMV-hNAGLU via systemic delivery for the treatment of MPS IIIB.
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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.