Evaluation of an AAV9-mini-dystrophin gene therapy candidate in a rat model of Duchenne muscular dystrophy
In: EISSN: 2329-0501 ; Molecular Therapy - Methods and Clinical Development ; https://inserm.hal.science/inserm-04240276 ; Molecular Therapy - Methods and Clinical Development, 2023, 30, pp.30-47. ⟨10.1016/j.omtm.2023.05.017⟩, 2023
Online
academicJournal
Zugriff:
International audience ; Duchenne muscular dystrophy (DMD) is an X-linked disease caused by loss-of-function mutations in the dystrophin gene and is characterized by muscle wasting and early mortality. Adeno-associated virus-mediated gene therapy is being investigated as a treatment for DMD. In the nonclinical study documented here, we determined the effective dose of fordadistrogene movaparvovec, a clinical candidate adeno-associated virus serotype 9 vector carrying a human mini-dystrophin transgene, after single intravenous injection in a dystrophin-deficient (DMDmdx) rat model of DMD. Overall, we found that transduction efficiency, number of muscle fibers expressing the human mini-dystrophin polypeptide, improvement of the skeletal and cardiac muscle tissue architecture, correction of muscle strength and fatigability, and improvement of diastolic and systolic cardiac function were directly correlated with the amount of vector administered. The effective dose was then tested in older DMDmdx rats with a more dystrophic phenotype similar to the pathology observed in older patients with DMD. Except for a less complete rescue of muscle function in the oldest cohort, fordadistrogene movaparvovec was also found to be therapeutically effective in older DMDmdx rats, suggesting that this product may be appropriate for evaluation in patients with DMD at all stages of disease.
Titel: |
Evaluation of an AAV9-mini-dystrophin gene therapy candidate in a rat model of Duchenne muscular dystrophy
|
---|---|
Autor/in / Beteiligte Person: | Le Guiner, Caroline ; Xiao, Xiao ; Larcher, Thibaut ; Lafoux, Aude ; Huchet, Corinne ; Toumaniantz, Gilles ; Adjali, Oumeya ; Anegon, Ignacio ; Remy, Séverine ; Grieger, Josh ; Li, Juan ; Farrokhi, Vahid ; Neubert, Hendrik ; Owens, Jane ; Mcintyre, Maritza ; Moullier, Philippe ; Samulski, R. Jude ; Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089 (TARGET) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE) ; Nantes Université - pôle Santé ; Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé ; Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ) ; Shanghai Jiao Tong University Shanghai ; Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher) ; École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) ; Expertise en Anatomie Pathologique (APEX) ; École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) ; Therassay Platform, CAPACITES ; Université de Nantes (UN) ; Nantes Université (Nantes Univ) ; Centre Hospitalier Universitaire de Nantes = Nantes University Hospital (CHU Nantes) ; Plate-forme Therassay Onco-Hématologie, Capacités UN Nantes ; Institut du Thorax Nantes ; Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology (U1064 Inserm - CR2TI) ; Team 2 : Cell and gene engineering in tolerance, fertility and regenerative medicine (Team 2 - U1064 Inserm - CR2TI) ; Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE) ; Institut de Transplantation et de Recherche en Transplantation CHU Nantes (ITERT) ; Bamboo Therapeutics Chapel Hill, NC, USA (BT - Pfizer) ; University of North Carolina at Chapel Hill NC, USA (UNC) ; Pfizer Inc. Andover, MA, USA ; Pfizer Inc. Cambridge, MA, USA ; University of North Carolina Chapel Hill (UNC) ; University of North Carolina System (UNC) |
Link: | |
Zeitschrift: | EISSN: 2329-0501 ; Molecular Therapy - Methods and Clinical Development ; https://inserm.hal.science/inserm-04240276 ; Molecular Therapy - Methods and Clinical Development, 2023, 30, pp.30-47. ⟨10.1016/j.omtm.2023.05.017⟩, 2023 |
Veröffentlichung: | HAL CCSD ; Nature Publishing Group, 2023 |
Medientyp: | academicJournal |
DOI: | 10.1016/j.omtm.2023.05.017 |
Schlagwort: |
|
Sonstiges: |
|