Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders
Issued Date
2022-09-23
Resource Type
eISSN
23752548
Scopus ID
2-s2.0-85138265688
Pubmed ID
36129972
Journal Title
Science Advances
Volume
8
Issue
38
Rights Holder(s)
SCOPUS
Bibliographic Citation
Science Advances Vol.8 No.38 (2022)
Suggested Citation
El Andari J., Renaud-Gabardos E., Tulalamba W., Weinmann J., Mangin L., Hong Pham Q., Hille S., Bennett A., Attebi E., Bourges E., Leborgne C., Guerchet N., Fakhiri J., Krämer C., Wiedtke E., McKenna R., Guianvarc'h L., Toueille M., Ronzitti G., Hebben M., Mingozzi F., VandenDriessche T., Agbandje-McKenna M., Müller O.J., Chuah M.K., Buj-Bello A., Grimm D. Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders. Science Advances Vol.8 No.38 (2022). doi:10.1126/sciadv.abn4704 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/86470
Title
Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders
Author(s)
El Andari J.
Renaud-Gabardos E.
Tulalamba W.
Weinmann J.
Mangin L.
Hong Pham Q.
Hille S.
Bennett A.
Attebi E.
Bourges E.
Leborgne C.
Guerchet N.
Fakhiri J.
Krämer C.
Wiedtke E.
McKenna R.
Guianvarc'h L.
Toueille M.
Ronzitti G.
Hebben M.
Mingozzi F.
VandenDriessche T.
Agbandje-McKenna M.
Müller O.J.
Chuah M.K.
Buj-Bello A.
Grimm D.
Renaud-Gabardos E.
Tulalamba W.
Weinmann J.
Mangin L.
Hong Pham Q.
Hille S.
Bennett A.
Attebi E.
Bourges E.
Leborgne C.
Guerchet N.
Fakhiri J.
Krämer C.
Wiedtke E.
McKenna R.
Guianvarc'h L.
Toueille M.
Ronzitti G.
Hebben M.
Mingozzi F.
VandenDriessche T.
Agbandje-McKenna M.
Müller O.J.
Chuah M.K.
Buj-Bello A.
Grimm D.
Author's Affiliation
Siriraj Hospital
Departement Cardiovasculaire Wetenschappen
Spark Therapeutics, Inc.
Deutsches Zentrum für Herz-Kreislauf-Forschung e. V.
Roche Pharma AG
Université d'Evry Val d'Essonne
Vrije Universiteit Brussel
Universität Heidelberg
University of Florida
Novartis International AG
Généthon
Universitätsklinikum Schleswig-Holstein Campus Kiel
DiNAQOR
Merck Life Science
LogicBio Therapeutics
Departement Cardiovasculaire Wetenschappen
Spark Therapeutics, Inc.
Deutsches Zentrum für Herz-Kreislauf-Forschung e. V.
Roche Pharma AG
Université d'Evry Val d'Essonne
Vrije Universiteit Brussel
Universität Heidelberg
University of Florida
Novartis International AG
Généthon
Universitätsklinikum Schleswig-Holstein Campus Kiel
DiNAQOR
Merck Life Science
LogicBio Therapeutics
Other Contributor(s)
Abstract
Bioengineering of viral vectors for therapeutic gene delivery is a pivotal strategy to reduce doses, facilitate manufacturing, and improve efficacy and patient safety. Here, we engineered myotropic adeno-associated viral (AAV) vectors via a semirational, combinatorial approach that merges AAV capsid and peptide library screens. We first identified shuffled AAVs with increased specificity in the murine skeletal muscle, diaphragm, and heart, concurrent with liver detargeting. Next, we boosted muscle specificity by displaying a myotropic peptide on the capsid surface. In a mouse model of X-linked myotubular myopathy, the best vectors-AAVMYO2 and AAVMYO3-prolonged survival, corrected growth, restored strength, and ameliorated muscle fiber size and centronucleation. In a mouse model of Duchenne muscular dystrophy, our lead capsid induced robust microdystrophin expression and improved muscle function. Our pipeline is compatible with complementary AAV genome bioengineering strategies, as demonstrated here with two promoters, and could benefit many clinical applications beyond muscle gene therapy.