Advances and challenges in gene therapy for dystrophic epidermolysis bullosa: Insights from therapeutic strategies and animal models

Abstract

Dystrophic epidermolysis bullosa (DEB) is a severe monogenic skin disorder resulting from mutations in the COL7A1 gene, which disrupts the synthesis of type VII collagen. This leads to impaired anchoring fibrils and results in dermoepidermal separation. The clinical manifestation of DEB varies significantly, ranging from localized blistering in milder forms to extensive blistering with subsequent severe complications such as vision loss and squamous cell carcinoma in more severe cases. Despite the recent approval of the first gene replacement therapy by the U.S. Food and Drug Administration, the majority of DEB patients still depend on palliative care, an indication of the continued unmet therapeutic needs. In the past two decades, there has been a rapid advancement of gene therapy techniques, extensive research efforts, and pre-clinical studies focusing on the correction of DNA, RNA, and protein defects specific to DEB. In this review, we provide a comprehensive update on the current state of gene engineering strategies for DEB, including gene replacement, pre-mRNA regulatory therapies, and gene editing techniques. In addition, this review critically evaluates the role and development of animal models in DEB research, which are crucial for the progression of therapeutic strategies. Our discussion aims to delineate the existing challenges and emphasize ongoing advancements in the gene therapy landscape for DEB, providing insights that may guide future research and clinical approaches.