ArticlePNAS nexus2023
Readministration of high-dose adeno-associated virus gene therapy vectors enabled by ImmTOR nanoparticles combined with B cell-targeted agents.
Article in PNAS nexus, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 13 citations in OpenAlex.
- Rapamycin nanoparticles mitigate anti-AAV antibody formation in a mouse model of ornithine transcarbamylase deficiency.Molecular therapy. Advances · 2026Article
- Preclinical pharmacology and toxicology study of an AAV8-tATP7B vector for Wilson's disease.Clinical and molecular hepatology · 2026Article
- Liver Gene Therapy in Fabry Disease Mice With Low Doses of rAAV2/8 Expressing a Codon-Optimized hGLA cDNA Results in Long-Term Disease Correction.Journal of inherited metabolic disease · 2026Article
- The co-delivery of Programmed Death 1 ligands enhances and prolongs rAAV-mediated gene expression in pre-immunized mice.Gene therapy · 2026Article
- Viral vector-based gene therapies in the clinic: An update.Bioengineering & translational medicine · 2026Review
- Emerging Technologies Tackling Adeno-Associated Viruses (AAV) Immunogenicity in Gene Therapy Applications.Pharmaceutics · 2025Review
- Use of CD19-targeted immune modulation to eradicate AAV-neutralizing antibodies.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- The curious case of AAV immunology.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Treating neuromuscular diseases: unveiling gene therapy breakthroughs and pioneering future applications.Journal of biomedical science · 2025Review
- Dihydroartemisinin decreases pre-existing neutralizing antibodies against adeno-associated virus in challenged mice.Frontiers in pharmacology · 2025Article
- rAAV expressing a COBRA-designed influenza hemagglutinin generates a protective and durable adaptive immune response with a single dose.Journal of virology · 2024Article
- Role of FoxP3Human gene therapy · 2024Review
- A comprehensive overview of tolerogenic vaccine adjuvants and their modes of action.Frontiers in immunology · 2024Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tolerogenic ImmTOR nanoparticles encapsulating rapamycin have been demonstrated to mitigate immunogenicity of adeno-associated virus (AAV) gene therapy vectors, enhance levels of transgene expression, and enable redosing of AAV at moderate vector doses of 2 to 5E12 vg/kg. However, recent clinical trials have often pushed AAV vector doses 10-fold to 50-fold higher, with serious adverse events observed at the upper range. Here, we assessed combination therapy of ImmTOR with B cell-targeting drugs for the ability to increase the efficiency of redosing at high vector doses. The combination of ImmTOR with a monoclonal antibody against B cell activation factor (aBAFF) exhibited strong synergy leading to more than a 5-fold to 10-fold reduction of splenic mature B cells and plasmablasts while increasing the fraction of pre-/pro-B cells. In addition, this combination dramatically reduced anti-AAV IgM and IgG antibodies, thus enabling four successive AAV administrations at doses up to 5E12 vg/kg and at least two AAV doses at 5E13 vg/kg, with the transgene expression level in the latter case being equal to that observed in control animals receiving a single vector dose of 1E14 vg/kg. Similar synergistic effects were seen with a combination of ImmTOR and a Bruton's tyrosine kinase inhibitor, ibrutinib. These results suggest that ImmTOR could be combined with B cell-targeting agents to enable repeated vector administrations as a potential strategy to avoid toxicities associated with vector doses above 1E14 vg/kg.
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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.