Rational immunosilencing of a promiscuous T-cell epitope in the capsid of an adeno-associated virus.

Autor: Bing SJ; Division of Gene Therapy 2, Office of Gene Therapy, Office of Therapeutic Products, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA., Seirup M; Promega Corporation, Madison, WI, USA., Hoang TT; Promega Corporation, Madison, WI, USA., Najera SS; Division of Gene Therapy 2, Office of Gene Therapy, Office of Therapeutic Products, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA., Britten C; Waters | Wyatt Technology, Santa Barbara, CA, USA., Warrington SL; Division of Gene Therapy 2, Office of Gene Therapy, Office of Therapeutic Products, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA., Chu SL; Division of Gene Therapy 2, Office of Gene Therapy, Office of Therapeutic Products, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA., Mazor R; Division of Gene Therapy 2, Office of Gene Therapy, Office of Therapeutic Products, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA. ronit.mazor@fda.hhs.gov.
Jazyk: angličtina
Zdroj: Nature biomedical engineering [Nat Biomed Eng] 2024 Feb; Vol. 8 (2), pp. 193-200. Date of Electronic Publication: 2023 Nov 23.
DOI: 10.1038/s41551-023-01129-8
Abstrakt: Owing to the immunogenicity of adeno-associated viruses (AAVs), gene therapies using AAVs face considerable obstacles. Here, by leveraging ex vivo T-cell assays, the prediction of epitope binding to major histocompatibility complex class-II alleles, sequence-conservation analysis in AAV phylogeny and site-directed mutagenesis, we show that the replacement of amino acid residues in a promiscuous and most immunodominant T-cell epitope in the AAV9 capsid with AAV5 sequences abrogates the immune responses of peripheral blood mononuclear cells to the chimaeric vector while preserving its functions, potency, cellular specificity, transduction efficacy and biodistribution. This rational approach to the immunosilencing of capsid epitopes promiscuously binding to T cells may be applied to other AAV vectors and epitope regions.
(© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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