Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders
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- Jihad El Andari
- Medical Faculty, Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Cluster of Excellence CellNetworks, University of Heidelberg, 69120 Heidelberg, Germany.
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- Edith Renaud-Gabardos
- Genethon, 91000 Evry, France.
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- Warut Tulalamba
- Department of Gene Therapy and Regenerative Medicine, Vrije Universiteit Brussel (VUB), Brussels 1090, Belgium.
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- Jonas Weinmann
- Medical Faculty, Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Cluster of Excellence CellNetworks, University of Heidelberg, 69120 Heidelberg, Germany.
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- Louise Mangin
- Genethon, 91000 Evry, France.
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- Quang Hong Pham
- Department of Gene Therapy and Regenerative Medicine, Vrije Universiteit Brussel (VUB), Brussels 1090, Belgium.
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- Susanne Hille
- University Hospital Schleswig-Holstein, Campus Kiel, Innere Medizin III, 24105 Kiel, Germany.
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- Antonette Bennett
- Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
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- Esther Attebi
- Genethon, 91000 Evry, France.
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- Emanuele Bourges
- Genethon, 91000 Evry, France.
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- Christian Leborgne
- Genethon, 91000 Evry, France.
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- Nicolas Guerchet
- Genethon, 91000 Evry, France.
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- Julia Fakhiri
- Medical Faculty, Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Cluster of Excellence CellNetworks, University of Heidelberg, 69120 Heidelberg, Germany.
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- Chiara Krämer
- Medical Faculty, Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Cluster of Excellence CellNetworks, University of Heidelberg, 69120 Heidelberg, Germany.
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- Ellen Wiedtke
- Medical Faculty, Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Cluster of Excellence CellNetworks, University of Heidelberg, 69120 Heidelberg, Germany.
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- Robert McKenna
- Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
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- Laurence Guianvarc’h
- Genethon, 91000 Evry, France.
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- Magali Toueille
- Genethon, 91000 Evry, France.
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- Giuseppe Ronzitti
- Genethon, 91000 Evry, France.
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- Matthias Hebben
- Genethon, 91000 Evry, France.
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- Federico Mingozzi
- Genethon, 91000 Evry, France.
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- Thierry VandenDriessche
- Department of Gene Therapy and Regenerative Medicine, Vrije Universiteit Brussel (VUB), Brussels 1090, Belgium.
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- Mavis Agbandje-McKenna
- Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
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- Oliver J. Müller
- University Hospital Schleswig-Holstein, Campus Kiel, Innere Medizin III, 24105 Kiel, Germany.
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- Marinee K. Chuah
- Department of Gene Therapy and Regenerative Medicine, Vrije Universiteit Brussel (VUB), Brussels 1090, Belgium.
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- Ana Buj-Bello
- Genethon, 91000 Evry, France.
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- Dirk Grimm
- Medical Faculty, Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Cluster of Excellence CellNetworks, University of Heidelberg, 69120 Heidelberg, Germany.
抄録
<jats:p>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.</jats:p>
収録刊行物
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- Science Advances
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Science Advances 8 (38), eabn4704-, 2022-09-23
American Association for the Advancement of Science (AAAS)