Gene transfer of µDys improved muscle resistance but did not reduce profibrotic signaling, indicating persistent fibrotic activity post-gene therapy in DMD MYOrganoids.
Does AAV-mediated microdystrophin gene transfer improve muscle function and reduce fibrotic signaling in human DMD MYOrganoids?
Human iPSC-derived DMD MYOrganoids co-cultured with fibroblasts successfully recapitulate muscle dysfunction and fibrotic activity, revealing that microdystrophin gene therapy improves muscle resistance but fails to fully resolve profibrotic signaling.
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Leading gene therapy approaches for Duchenne muscular dystrophy (DMD) using AAV-mediated delivery of microdystrophin (µDys) have shown partial efficacy in patients, contrasting with the favorable outcomes observed in animal models. The identification of effective therapeutic strategies could be accelerated by using human high-throughput DMD models that replicate the molecular complexity driving pathology for accurate screening. To face this challenge, we develop MYOrganoids, an engineered muscle platform derived from patient-induced pluripotent stem cells (iPSC), recapitulating critical hallmarks of DMD, such as fibrosis and muscle dysfunction. We show that co-culture of fibroblasts with iPSC-derived muscle cells during organoid generation is pivotal for functional maturation and muscle force evaluation upon eccentric contractions. Notably, incorporation of DMD fibroblasts induced phenotypic exacerbation in DMD MYOrganoids by unraveling of fibrotic signature and fatiguability through cell-contact and paracrine mechanisms. We then exploited our system to interrogate gene therapy efficacy in this severe context. Although µDys gene transfer improves muscle resistance and partially restores membrane stability, it fails to reduce profibrotic signaling. These findings highlight the persistence of fibrotic activity post-gene therapy in our system, a limitedly explored aspect in DMD models, and provide the opportunity to study mechanisms of dysregulated cellular communication and empower gene therapy efficacy.
Palmieri et al. (Fri,) reported a other. Gene transfer of µDys improved muscle resistance but did not reduce profibrotic signaling, indicating persistent fibrotic activity post-gene therapy in DMD MYOrganoids.