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- Title
An engineered AAV targeting integrin alpha V beta 6 presents improved myotropism across species.
- Authors
Vu Hong, Ai; Suel, Laurence; Petat, Eva; Dubois, Auriane; Le Brun, Pierre-Romain; Guerchet, Nicolas; Veron, Philippe; Poupiot, Jérôme; Richard, Isabelle
- Abstract
Current adeno-associated virus (AAV) gene therapy using nature-derived AAVs is limited by non-optimal tissue targeting. In the treatment of muscular diseases (MD), high doses are often required but can lead to severe adverse effects. Here, we rationally design an AAV capsid that specifically targets skeletal muscle to lower treatment doses. We computationally integrate binding motifs of human integrin alphaV beta6, a skeletal muscle receptor, into a liver-detargeting capsid. Designed AAVs show higher productivity and superior muscle transduction compared to their parent. One variant, LICA1, demonstrates comparable muscle transduction to other myotropic AAVs with reduced liver targeting. LICA1's myotropic properties are observed across species, including non-human primate. Consequently, LICA1, but not AAV9, effectively delivers therapeutic transgenes and improved muscle functionality in two mouse MD models (male mice) at a low dose (5E12 vg/kg). These results underline the potential of our design method for AAV engineering and LICA1 variant for MD gene therapy. Gene therapy using adeno-associated virus (AAV) has shown promise for treating genetic diseases yet limited by inefficient delivery. Here, the authors develop an AAV variant targeting specifically the skeletal muscle and enabling effective gene therapy for muscle diseases at significantly lower doses.
- Subjects
GENE therapy; ADENO-associated virus; SKELETAL muscle; MUSCLE diseases; METHODS engineering
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-52002-4