An engineered AAV targeting integrin alpha V beta 6 presents improved myotropism across species

Ai Vu Hong (), Laurence Suel, Eva Petat, Auriane Dubois, Pierre-Romain Le Brun, Nicolas Guerchet, Philippe Veron, Jérôme Poupiot and Isabelle Richard ()
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Ai Vu Hong: 1 bis rue de l’internationale
Laurence Suel: 1 bis rue de l’internationale
Eva Petat: 1 bis rue de l’internationale
Auriane Dubois: 1 bis rue de l’internationale
Pierre-Romain Le Brun: 1 bis rue de l’internationale
Nicolas Guerchet: 1 bis rue de l’internationale
Philippe Veron: 1 bis rue de l’internationale
Jérôme Poupiot: 1 bis rue de l’internationale
Isabelle Richard: 1 bis rue de l’internationale

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52002-4

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