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Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders

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...

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Main Authors: El Andari, Jihad (Author) , Renaud-Gabardos, Edith (Author) , Tulalamba, Warut (Author) , Weinmann, Jonas (Author) , Mangin, Louise (Author) , Pham, Quang Hong (Author) , Hille, Susanne (Author) , Bennett, Antonette (Author) , Attebi, Esther (Author) , Bourges, Emanuele (Author) , Leborgne, Christian (Author) , Guerchet, Nicolas (Author) , Fakhiri, Julia (Author) , Krämer, Chiara (Author) , Wiedtke, Ellen (Author) , McKenna, Robert (Author) , Guianvarc’h, Laurence (Author) , Toueille, Magali (Author) , Ronzitti, Giuseppe (Author) , Hebben, Matthias (Author) , Mingozzi, Federico (Author) , VandenDriessche, Thierry (Author) , Agbandje-McKenna, Mavis (Author) , Müller, Oliver J. (Author) , Chuah, Marinee K. (Author) , Buj-Bello, Ana (Author) , Grimm, Dirk (Author)
Format: Article (Journal)
Language:English
Published: 21 September 2022
In: Science advances
Year: 2022, Volume: 8, Issue: 38, Pages: 1-21
ISSN:2375-2548
DOI:10.1126/sciadv.abn4704
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1126/sciadv.abn4704
Verlag, lizenzpflichtig, Volltext: https://www.science.org/doi/10.1126/sciadv.abn4704
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Author Notes:Jihad El Andari, Edith Renaud-Gabardos, Warut Tulalamba, Jonas Weinmann, Louise Mangin, Quang Hong Pham, Susanne Hille, Antonette Bennett, Esther Attebi, Emanuele Bourges, Christian Leborgne, Nicolas Guerchet, Julia Fakhiri, Chiara Krämer, Ellen Wiedtke, Robert McKenna, Laurence Guianvarc’h, Magali Toueille, Giuseppe Ronzitti, Matthias Hebben, Federico Mingozzi, Thierry VandenDriessche, Mavis Agbandje-McKenna, Oliver J. Müller, Marinee K. Chuah, Ana Buj-Bello, Dirk Grimm
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Summary: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.
Item Description:Gesehen am 06.02.2023
Physical Description:Online Resource
ISSN:2375-2548
DOI:10.1126/sciadv.abn4704

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