ArticleJCI insight2019
Dual muscle-liver transduction imposes immune tolerance for muscle transgene engraftment despite preexisting immunity.
Article in JCI insight, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 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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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
17 citing papers in PubMed, 21 citations in OpenAlex.
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- Synergism of dual AAV gene therapy and rapamycin rescues GSDIII phenotype in muscle and liver.JCI insight · 2024Article
- AAV Immunotoxicity: Implications in Anti-HBV Gene Therapy.Microorganisms · 2023Review
- Tumor antigen-loaded AAV vaccine drives protective immunity in a melanoma animal model.Molecular therapy. Methods & clinical development · 2023Article
- Neuropilin-1 cooperates with PD-1 in CD8iScience · 2022Article
- Chimeric Mice Engrafted With Canine Hepatocytes Exhibits Similar AAV Transduction Efficiency to Hemophilia B Dog.Frontiers in pharmacology · 2022Article
- Hepatic expression of GAA results in enhanced enzyme bioavailability in mice and non-human primates.Nature communications · 2021Article
- Cas9-directed immune tolerance in humans-a model to evaluate regulatory T cells in gene therapy?Gene therapy · 2021Review
- Enhancement of the Tolerogenic Phenotype in the Liver by ImmTOR Nanoparticles.Frontiers in immunology · 2021Article
- Adeno-Associated Viruses (AAV) and Host Immunity - A Race Between the Hare and the Hedgehog.Frontiers in immunology · 2021Review
- Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back.Journal of personalized medicine · 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
- Adeno-associated viral vector-mediated immune responses: Understanding barriers to gene delivery.Pharmacology & therapeutics · 2020Review
- Human Immune Responses to Adeno-Associated Virus (AAV) Vectors.Frontiers in immunology · 2020Review
- Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV.Frontiers in immunology · 2020Article
- Role of Regulatory T Cell and Effector T Cell Exhaustion in Liver-Mediated Transgene Tolerance in Muscle.Molecular therapy. Methods & clinical development · 2019Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Immune responses to therapeutic transgenes are a potential hurdle to treat monogenic muscle disorders. These responses result from the neutralizing activity of transgene-specific B cells and cytotoxic T cells recruited upon gene transfer. We explored here how dual muscle-liver expression of a foreign transgene allows muscle transgene engraftment after adenoassociated viral vector delivery. We found in particular that induction of transgene-specific tolerance is imposed by concurrent muscle and liver targeting, resulting in the absence of CD8+ T cell responses to the transgene. This tolerance can be temporally decoupled, because transgene engraftment can be achieved in muscle weeks after liver transduction. Importantly, transgene-specific CD8+ T cell tolerance can be established despite preexisting immunity to the transgene. Whenever preexisting, transgene-specific CD4+ and CD8+ memory T cell responses are present, dual muscle-liver transduction turns polyclonal, transgene-specific CD8+ T cells into typically exhausted T cells with high programmed cell death 1 (PD-1) expression and lack of IFN-γ production. Our results demonstrate that successful transduction of muscle tissue can be achieved through liver-mediated control of humoral and cytotoxic T cell responses, even in the presence of preexisting immunity to the muscle-associated transgene.
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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.