Reframing fibrosis as a barrier to regeneration and gene delivery in muscular diseases

Gene replacement therapies for muscular dystrophies show promise in preclinical models but often fail in clinical settings. A major difference between animal models and human pathology is the extent of fibrosis observed. Progressive and irreversible fibrosis needs to be targeted before or alongside genetic strategies. Fibrosis limits muscle function through a collagen-rich extracellular matrix (ECM) that forms a stiff barrier impeding penetration of gene therapy vectors, such as adeno-associated viruses (AAVs). It disrupts the satellite cell niche, compromising activation, proliferation, and differentiation. Even with successful gene delivery, regeneration in fibrotic muscle is severely impaired. Recent reports of acute liver toxicity leading to deaths in gene therapy trials using the AAVrh74 vector underscore the risks associated with high systemic AAV doses. If fibrosis can be alleviated, effective transduction might be achieved with lower vector quantities in a single therapeutic dose, reducing the systemic risks. Anti-fibrotic agents are being explored to counteract disease progression. Modulators of ECM maturation offer novel therapeutic targets. However, pleiotropic and context-dependent roles of these mediators complicate translation. Therapies must target pathological ECM remodeling without disrupting essential physiology elsewhere. In this Review, we examine therapeutic efforts targeting skeletal muscle dystrophies and emphasize fibrosis as a major barrier to gene and regenerative therapies. We highlight the need for a deeper investigation into fibrotic pathways, modulators, and extracellular maturation processes and propose that these underexplored areas may yield novel therapeutic targets for muscular dystrophies. A fibrosis-aware therapeutic framework that integrates insights across systems and pathologies is critical for improving treatment outcomes in skeletal muscle disorders.