ArticleMolecular therapy : the journal of the American Society of Gene Therapy2020
Muscle-Directed Delivery of an AAV1 Vector Leads to Capsid-Specific T Cell Exhaustion in Nonhuman Primates and Humans.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 43 citations in OpenAlex.
- Taming immune responses to AAV gene therapy by programmed in vivo Treg expansion.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Overcoming host immune responses to an AAV-delivered HIV-1 bNAb in rhesus macaques mediated by co-delivery of PD-L1.bioRxiv : the preprint server for biology · 2026Article
- Cancer cells accelerate exhaustion of persistently activated mouse CD4Oncoimmunology · 2025Article
- Transient rapamycin treatment avoids unwanted host immune responses toward AAV-delivered anti-HIV antibodies.Nature communications · 2025Article
- Can Sex-based Variations in the Immune Responses to AAV Gene Therapy Affect Safety and Efficacy? A Review of Current Understanding.The AAPS journal · 2025Review
- Teaching an old vector new tricks: the surprising versatility of AAV vaccines.Journal of virology · 2025Review
- AAV1.NT3 gene therapy mitigates the severity of autoimmune encephalomyelitis in the mouse model for multiple sclerosis.Gene therapy · 2025Article
- Incomplete elimination of viral genomes is associated with chronic inflammation in nonhuman primate livers after AAV-mediated gene transfer.Gene therapy · 2025Article
- Immune-driven gene expression loss following intramuscular AAV delivery to non-human primates is only transient.Molecular therapy. Methods & clinical development · 2025Article
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- A peptide conjugate enables systemic injection of the morpholino inducer and more durable induction of T3H38 ribozyme-controlled AAV transgene in mice.Gene therapy · 2025Article
- Biomimetic Brain-Targeted Drug Delivery System for the Treatment of Brain Diseases.Current drug delivery · 2025Review
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- Role of FoxP3Human gene therapy · 2024Review
- tRNA therapeutics for genetic diseases.Nature reviews. Drug discovery · 2024Review
- Interspecies Scaling of Transgene Products for Viral Vector Gene Therapies: Method Assessment Using Data from Eleven Viral Vectors.The AAPS journal · 2023Article
- Transcriptomic Analysis Reveals the Inability of Recombinant AAV8 to Activate Human Monocyte-Derived Dendritic Cells.International journal of molecular sciences · 2023Article
- Adeno-associated virus-vectored delivery of HIV biologics: the promise of a "single-shot" functional cure for HIV infection.Journal of virus eradication · 2023Article
- The HLA class I immunopeptidomes of AAV capsid proteins.Frontiers in immunology · 2023Article
- Immunogenicity assessment of AAV-based gene therapies: An IQ consortium industry white paper.Molecular therapy. Methods & clinical development · 2022Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
With the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approvals for Zolgensma, Luxturna, and Glybera, recombinant adeno-associated viruses (rAAVs) are considered efficient tools for gene transfer. However, studies in animals and humans demonstrate that intramuscular (IM) AAV delivery can trigger immune responses to AAV capsids and/or transgenes. IM delivery of rAAV1 in humans has also been described to induce tolerance to rAAV characterized by the presence of capsid-specific regulatory T cells (Tregs) in periphery. To understand mechanisms responsible for tolerance and parameters involved, we tested 3 muscle-directed administration routes in rhesus monkeys: IM delivery, venous limb perfusion, and the intra-arterial push and dwell method. These 3 methods were well tolerated and led to transgene expression. Interestingly, gene transfer in muscle led to Tregs and exhausted T cell infiltrates in situ at both day 21 and day 60 post-injection. In human samples, an in-depth analysis of the functionality of these cells demonstrates that capsid-specific exhausted T cells are detected after at least 5 years post-vector delivery and that the exhaustion can be reversed by blocking the checkpoint pathway. Overall, our study shows that persisting transgene expression after gene transfer in muscle is mediated by Tregs and exhausted T cells.
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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.