B7 - Musculo-skeletal Diseases
670: Disease Exacerbation in 3D MYOtissues Derived From Duchenne Muscular Dystrophy iPSC Reveals Muscle Strength Loss and Enables Gene Therapy Screening
Type: Poster Session
Poster Board Number: 670
Presentation Details
Session Title: Wednesday Posters: Musculo-Skeletal Diseases
Duchenne muscular dystrophy (DMD) is a lethal muscle-wasting disease caused by the absence of Dystrophin, a protein essential to preserve muscle integrity continuously challenged by contractions. Gene therapy utilizing adeno-associated virus (AAV) to deliver truncated forms of dystrophin (µDys) is currently the most promising therapeutic approach. However, the therapeutic outcome in treated patients has not been as successful as anticipated by animal studies, underscoring the need for improved and high-throughput models for fast and accurate prediction of human response. Among the in vitro cellular models, organoid-like structures are becoming an appealing resource for disease modeling and replacement of animal models. Here, we describe the generation of MYOtissues, an in vitro 3D muscle platform based on direct myogenic conversion of human induced pluripotent stem cells (iPSC) and inclusion of fibroblasts to ensure proper muscle structure. MYOtissues derived from DMD-iPSC including DMD fibroblasts, show exacerbated pathogenic hallmarks such as fibrosis and muscle force loss, across the different DMD iPSC cell lines employed, independently from the genetic background of the DMD fibroblasts used. As proof of the suitability of our system for gene therapy screening, we showed that AAV9-mediated µDys gene transfer in DMD-MYOtissues improved muscle resistance and recovered, although only partially, membrane stability with consequent reduction of the inflammatory environment. Our data, obtained in three control and DMD cell lines including isogenic controls, were supported by transcriptomic analysis which demonstrated an amelioration of mechano-stability and inflammatory hallmarks but also reveals that only a partial correction of the deregulated pathways in DMD was achieved. This study highlights the suitability of our human in vitro system for gene therapy screening and supports the need for developing more efficient gene therapy strategies for DMD patients.
Plain Language Summary
Duchenne muscular dystrophy (DMD) is a serious muscle-wasting disease caused by the absence of dystrophin, a protein crucial for maintaining muscle integrity during contractions. Unfortunately, there is currently no resolutive treatment for DMD. A major challenge is posed by the lack of a human model for the disease that can accurately predict if and how potential treatments will work in patients. In our research, we created artificial 3D muscle tissues, called MYOtissues, suitable for testing the efficiency of potential therapeutic candidates for DMD. Remarkably, we found that treating MYOtissues with the currently used gene therapy approach micro-dystrophin, only partially reversed the disease's harmful effects. Our study emphasizes the usefulness of our human in vitro system for testing treatments and underscores the need to develop more effective therapeutical strategies for DMD patients.
Laura Palmieri1,2, Louna Pili1,2, Abbass Jaber1,2, Melissa Moula1, Ai Vu Hong1,2, Riyad El-Khoury1,2,3, Guy Brochier3,4, Anne Bigot5, David Israeli1,2, Isabelle Richard1,2, Sonia Albini1,2
1GENETHON, Evry, France,2Université Paris-Saclay, Univ Evry, Integrare Research Unit UMR_S951, Evry, France,3Institut de Myologie, Paris, France,4AP-HP, Centre de Référence de Pathologie Neuromusculaire Nord/Est/Ile de France, Paris, France,5Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie, Paris, France"
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