Gene Therapy for Dystrophic Epidermolysis Bullosa.

Dystrophic epidermolysis bullosa (DEB) is a rare, debilitating genodermatosis caused by loss-of-function variants in COL7A1, resulting in type VII collagen (C7) deficiency and defective anchoring fibrils, which are essential for dermal-epidermal adhesion. COL7A1 is a large gene, and C7 is synthesized by both keratinocytes and fibroblasts, and extracellularly secreted, where it forms a supramolecular network that stabilizes the dermal-epidermal junction. Human genotype-phenotype correlations suggest that residual C7 expression (~10% of normal levels) may confer a milder disease phenotype, whereas complete absence results in generalized skin fragility with scarring and systemic complications. Thus, restoring C7 expression remains a central therapeutic objective. Since the discovery of COL7A1, thousands of pathogenic variants have been described, including amino acid substitutions in the triple-helical domain that allow partial C7 function, whereas null alleles are associated with severe phenotypes. Gene- and cell-based strategies have evolved to address the large COL7A1 size and delivery challenges. Ex vivo gene/cell therapies (keratinocytes or fibroblasts engineered to express COL7A1) have demonstrated partial, wound-specific C7 restoration but with durability limitations, as grafted cells may be outcompeted or lose transgene expression over time; select patients show sustained anchoring fibril formation and improved wound healing; however, long-term outcomes remain variable. In vivo topical gene therapy has achieved clinically meaningful wound closure in DEB, illustrating a paradigm shift toward accessible and patient-friendly therapeutic approaches, albeit with real-world considerations on durability and wound recurrence. A multidisciplinary framework integrating EB expert centers, drug-delivery pharmacy services, wound management, and patient-support programs can further enhance treatment access and adherence. General factors such as nutritional status, infection and comorbidities also influence both wound healing and the response to gene therapy. Revertant mosaicism offers a natural gene-therapy substrate: cultured epidermal autografts derived from revertant patches have yielded substantial, yet heterogeneous, epithelization, with outcomes contingent on revertant cell proportion and culture fidelity. Collectively, these advances highlight the emerging potential of gene- and cell-based therapies to achieve durable disease modification in DEB.