Immune-driven gene expression loss following intramuscular AAV delivery to non-human primates is only transient

Bibliographic Details
Title:	Immune-driven gene expression loss following intramuscular AAV delivery to non-human primates is only transient
Authors:	Malo Journou, Marie Devaux, Nicolas Jaulin, Virginie Pichard, Mercedes Segovia, Aurélie Moreau, Johanne Le Duff, Maria Cristina Cuturi, Mickaël Guilbaud, Oumeya Adjali
Source:	Molecular Therapy: Methods & Clinical Development, Vol 33, Iss 1, Pp 101409- (2025)
Publisher Information:	Elsevier, 2025.
Publication Year:	2025
Collection:	LCC:Genetics LCC:Cytology
Subject Terms:	AAV, non-human primate, intramuscular, gene transfer, transitory loss, immune response, Genetics, QH426-470, Cytology, QH573-671
More Details:	Recombinant adeno-associated virus (rAAV) vectors stand out as highly promising for in vivo gene transfer, particularly in targeting the skeletal muscle for treating muscular genetic diseases or secreting therapeutic factors. Despite the simplicity and efficacy of the established intramuscular (IM) route, it has been often associated with an immune-induced rapid loss of transgene expression, in particular in large animal models, and generally considered irreversible as a consequence of a cytotoxic elimination of transduced cells. Here, we report in a non-human primate model that transgene expression loss after IM delivery of an rAAV1 expressing an immunogenic protein is only transient, with the re-expression of the transgene lasting up to 5 years post-injection. We show that the recovery of transgene expression is due to persisting viral genomes in the injected muscles despite the detection of peripheral anti-transgene cellular immunity. Persisting genomes were observed in the presence of infiltrated mononuclear CD8 and CD4 T lymphocytes, among which we were able to detect FoxP3+ regulatory cells. This is to our knowledge the first report of a transient immune-mediated loss of gene expression in a large animal model after rAAV delivery that should shed new light on the issue of rAAV vector immunogenicity.
Document Type:	article
File Description:	electronic resource
Language:	English
ISSN:	2329-0501
Relation:	http://www.sciencedirect.com/science/article/pii/S232905012500004X; https://doaj.org/toc/2329-0501
DOI:	10.1016/j.omtm.2025.101409
Access URL:	https://doaj.org/article/0293b65e53c641da885980f57002c9b3
Accession Number:	edsdoj.0293b65e53c641da885980f57002c9b3
Database:	Directory of Open Access Journals

More Details
ISSN:	23290501
DOI:	10.1016/j.omtm.2025.101409
Published in:	Molecular Therapy: Methods & Clinical Development
Language:	English