Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector

TLDR

Muscle-directed gene transfer is explored for metabolic diseases, but prior vector approaches yielded transient expression because of transgene silencing or immune responses. The study used a recombinant AAV vector encoding lacZ delivered to muscle of immunocompetent mice, and molecular analysis indicates that episomal vector DNA converts into high‑molecular‑weight genomic DNA, supporting persistence. The lacZ reporter was efficiently transduced and expressed without cellular immune response, persisting for over 1.5 years, marking the first demonstration of long‑term gene transduction in mammalian muscle without immune modulation.

Abstract

Muscle-directed gene transfer is being considered for the treatment of several metabolic diseases, including hemophilia and Duchene's muscular dystrophy. Previous efforts to target this tissue for somatic delivery with various vector systems have resulted in transient expression due to silencing of the transgene or to an immune response against the vector-transduced cells. We introduced recombinant adeno-associated virus vector (rAAV) carrying a lacZ reporter into muscle tissue of immunocompetent mice. The lacZ reporter gene was efficiently transduced and expressed with no evidence of a cellular immune response. Moreover, gene expression persisted for more than 1.5 years. Molecular characterization of rAAV vector DNA suggests a mechanism for persistence, since vector episomes convert to high-molecular-weight genomic DNA. These data provide the first report for establishing long-term gene transduction into mammalian muscle cells in vivo without the need for immune modulation of the organism.