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Article Dans Une Revue Science Advances Année : 2022

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

Jihad El Andari
Warut Tulalamba
  • Fonction : Auteur
Jonas Weinmann
  • Fonction : Auteur
Louise Mangin
Quang Hong Pham
  • Fonction : Auteur
Susanne Hille
  • Fonction : Auteur
Antonette Bennett
Esther Attebi
  • Fonction : Auteur
Emanuele Bourges
  • Fonction : Auteur
Christian Leborgne
Nicolas Guerchet
  • Fonction : Auteur
Julia Fakhiri
  • Fonction : Auteur
Chiara Krämer
  • Fonction : Auteur
Ellen Wiedtke
  • Fonction : Auteur
Robert Mckenna
Laurence Guianvarc’h
Magali Toueille
Matthias Hebben
Federico Mingozzi
Thierry Vandendriessche
  • Fonction : Auteur
Mavis Agbandje-Mckenna
  • Fonction : Auteur
Oliver Müller
Marinee Chuah
  • Fonction : Auteur
Ana Buj-Bello
Dirk Grimm

Résumé

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.
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Dates et versions

hal-04273243 , version 1 (07-11-2023)

Identifiants

  • HAL Id : hal-04273243 , version 1

Citer

Jihad El Andari, Edith Renaud-Gabardos, Warut Tulalamba, Jonas Weinmann, Louise Mangin, et al.. Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders. Science Advances , 2022, 8 (38). ⟨hal-04273243⟩
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