ArticleScience translational medicine2021
Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses.
Article in Science translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 150 papers, 1 of them a synthesis that pooled it.
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.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
150 citing papers in PubMed, 1 synthesis or guideline pooled it, 196 citations in OpenAlex.
- Retinal Viral Gene Therapy: Impact of Route of Administration on Serious Adverse Events-A Systematic Review.Clinical & experimental ophthalmology · 2025Pooled it
- Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A.The New England journal of medicine · 2021Trial
- Targeted AAV gene therapy for neuroblastoma via direct capsid-antibody coupling.EMBO molecular medicine · 2026Article
- Host Endoplasmic Reticulum Stress and Interferon Responses Contribute to AAV-Induced Ocular Toxicity.bioRxiv : the preprint server for biology · 2026Article
- RNA splicing and cardiovascular disease: a guide for cardiologists.European heart journal · 2026Review
- Article
- The Molecular Basis of Ocular Aging: Mechanisms, Pathologies, and Emerging Therapeutics.Investigative ophthalmology & visual science · 2026Review
- Attenuating AAV-triggered innate immunity in the adult mouse nervous systemActa pharmaceutica Sinica. B · 2026Article
- Ferumoxytol enhances NF-κB-responsive GBA-targeted ferroptosis gene therapy in acute myeloid leukemia.Journal of nanobiotechnology · 2026Article
- Adeno-associated virus-induced neurotoxicity is prevented by CpG depletion.Molecular therapy. Advances · 2026Article
- AAV NRF2 gene therapy preserves retinal structure and function in rodent models of oxidative damage.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Engineering challenges and translational opportunities in emerging gene delivery platforms.Nature biomedical engineering · 2026Review
- Microglia-independent rAAV-induced inflammation causes persistent ocular immune dysregulation rescued by S1P receptor modulation.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- RNA-Based Therapies for Treating Monogenic Cardiomyopathies.The Canadian journal of cardiology · 2026Review
- Interindividual variability in immune response to AAV ocular gene delivery across species impedes immunomonitoring.JCI insight · 2026Article
- Deaths in gene therapy of Duchenne muscular dystrophy and other diseases: Underlying mechanisms and mitigating strategies.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Review
- Self-inactivating AAV-CRISPR at different ages enables sustained amelioration of Huntington's disease deficits in BAC226Q mice.Science advances · 2026Article
- Adeno-Associated Virus Toxicity in Duchenne Muscular Dystrophy: Mechanisms and Clinical Considerations.Genes · 2026Review
- Heterologous prime-boost immunization of AAV-based neoantigen cancer vaccine induces anti-tumor immunity to inhibit tumor growth and relapse.Cancer immunology, immunotherapy : CII · 2026Article
- Lipid-nanoparticle-mediated base editing of the trabecular meshwork rescues glaucoma in vivo.JCI insight · 2026Article
90 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
41 authors at 10 institutions in 3 countries.
Funding
Abstract
Nucleic acids are used in many therapeutic modalities, including gene therapy, but their ability to trigger host immune responses in vivo can lead to decreased safety and efficacy. In the case of adeno-associated viral (AAV) vectors, studies have shown that the genome of the vector activates Toll-like receptor 9 (TLR9), a pattern recognition receptor that senses foreign DNA. Here, we engineered AAV vectors to be intrinsically less immunogenic by incorporating short DNA oligonucleotides that antagonize TLR9 activation directly into the vector genome. The engineered vectors elicited markedly reduced innate immune and T cell responses and enhanced gene expression in clinically relevant mouse and pig models across different tissues, including liver, muscle, and retina. Subretinal administration of higher-dose AAV in pigs resulted in photoreceptor pathology with microglia and T cell infiltration. These adverse findings were avoided in the contralateral eyes of the same animals that were injected with the engineered vectors. However, intravitreal injection of higher-dose AAV in macaques, a more immunogenic route of administration, showed that the engineered vector delayed but did not prevent clinical uveitis, suggesting that other immune factors in addition to TLR9 may contribute to intraocular inflammation in this model. Our results demonstrate that linking specific immunomodulatory noncoding sequences to much longer therapeutic nucleic acids can "cloak" the vector from inducing unwanted immune responses in multiple, but not all, models. This "coupled immunomodulation" strategy may widen the therapeutic window for AAV therapies as well as other DNA-based gene transfer methods.
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What OpenQuestion holds
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.