Evaluation of an AAV9-mini-dystrophin gene therapy candidate in a rat model of Duchenne muscular dystrophy

Caroline Le Guiner (1) , Xiao Xiao (2) , Thibaut Larcher (3, 4) , Aude Lafoux (5) , Corinne Huchet (6, 1, 7, 8) , Gilles Toumaniantz (9) , Oumeya Adjali (1) , Ignacio Anegon (10, 11, 12) , Séverine Remy (11, 10, 12) , Josh Grieger (13) , Juan Li (14) , Vahid Farrokhi (15) , Hendrik Neubert (15) , Jane Owens (16) , Maritza Mcintyre (13) , Philippe Moullier (1) , R. Jude Samulski (17)

1 TARGET - Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques / Translational Research in Gene Therapy - UMR_S 1089
2 Shanghai Jiao Tong University [Shanghai]
3 PAnTher - Physiopathologie Animale et bioThérapie du muscle et du système nerveux
4 APEX - Expertise en Anatomie Pathologique
5 Therassay Platform, CAPACITES
6 Nantes Univ - Nantes Université
7 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
8 Plate-forme Therassay Onco-Hématologie, Capacités [UN Nantes]
9 Institut du Thorax [Nantes]
10 U1064 Inserm - CR2TI - Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology
11 Team 2 - U1064 Inserm - CR2TI - Team 2 : Cell and gene engineering in tolerance, fertility and regenerative medicine
12 ITERT - Institut de Transplantation et de Recherche en Transplantation [CHU Nantes]
13 BT - Pfizer - Bamboo Therapeutics [Chapel Hill, NC, USA]
14 UNC - University of North Carolina at Chapel Hill [NC, USA]
15 Pfizer Inc. [Andover, MA, USA]
16 Pfizer Inc. [Cambridge, MA, USA]
17 UNC - University of North Carolina [Chapel Hill]

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.

Keywords: DMDmdx rat; Duchenne muscular dystrophy; age; dose study; gene therapy; mini-dystrophin; recombinant adeno-associated virus

Domains: Life Sciences [q-bio]

Caroline Le Guiner, Xiao Xiao, Thibaut Larcher, Aude Lafoux, Corinne Huchet, et al.. Evaluation of an AAV9-mini-dystrophin gene therapy candidate in a rat model of Duchenne muscular dystrophy. Molecular Therapy - Methods and Clinical Development, 2023, 30, pp.30-47. ⟨10.1016/j.omtm.2023.05.017⟩. ⟨inserm-04240276⟩