Pre-Existing Anti-Adeno-Associated Virus Immunity in Gene Therapy: Mechanisms, Challenges, and Potential Solutions.
Level 5 - mechanism / opinion, no new human data
Narrative review of mechanisms and mitigation strategies with no new human or experimental data.
PubMed 40985164 · doi:10.1177/10430342251378524
What was done
This narrative review synthesized existing literature on the immunological barriers to adeno-associated virus (AAV) gene therapy. It evaluated mechanisms of immune detection and clearance—including pattern recognition receptors, complement activation, and neutralizing antibodies—and outlined host, serotype, and delivery factors that alter transduction. It proposed a three-pronged framework classifying mitigation strategies into immune-focused, delivery-focused, and capsid-focused categories.
What was found
The abstract reports no quantitative metrics or effect sizes. It qualitatively summarizes the mechanisms driving vector clearance and details three intervention categories: (1) immune-focused strategies (e.g., plasmapheresis, immunoadsorption, enzymatic antibody cleavage, B cell depletion, and corticosteroids); (2) delivery-focused strategies (e.g., localized or intrathecal delivery, immune-privileged targeting, and administration timing); and (3) capsid-focused strategies (e.g., rational capsid engineering, empty capsid decoys, and AAV-specific regulatory T cells).
Why it matters
Pre-existing neutralizing antibodies exclude a substantial portion of patients from receiving approved and investigational AAV gene therapies. Structuring mitigation techniques into clear operational categories helps guide preclinical development toward re-dosable and broader-access vector platforms.
Limits
As a narrative review, the paper introduces no new empirical data, clinical trials, or systematic meta-analytic syntheses. The abstract provides no quantitative comparisons of the efficacy, safety, or feasibility of the proposed mitigation approaches.
Cited by
- supports Introducing genes into cells using viral vectors or plasmids can cause engineered tissues to express foreign antigens that trigger immune rejection upon transplantation.