Epidermolysis bullosa (EB) is a rare, monogenic skin disease characterized by the formation of extensive blisters and wounds on the skin and mucous membranes due to minimal mechanical stress. The disease is caused by genetic mutations in genes encoding proteins essential for dermal-epidermal connectivity, leading to severe clinical manifestations and reduced life expectancy. Recent breakthroughs in gene therapy have provided promising outcomes for EB patients. Two gene therapeutic approaches are currently showing promise: gene replacement and gene editing. **Gene Replacement:** - **Ex Vivo Gene Therapy:** This approach involves isolating patient skin cells, treating them in vitro to correct the genetic mutation, and then generating autologous skin grafts for transplantation. Successful clinical trials have demonstrated improved wound healing and stable skin integrity in patients with junctional EB (JEB) and recessive dystrophic EB (RDEB). - **In Vivo Gene Therapy:** The first FDA-approved gene therapy for EB, Vyuvek™ (beremagene geperuparc, B-VEC), is a topical treatment for RDEB wounds. It uses a non-replicative herpes simplex virus type 1 vector to deliver full-length collagen type VII (C7) cDNA. Clinical trials showed significant improvements in wound closure and safety, leading to FDA approval. **Gene Editing:** - **CRISPR/Cas9:** This is the most advanced gene editing tool, enabling precise and targeted correction of mutations. CRISPR/Cas9 systems, including base editing (BE) and prime editing (PE), have shown promise in correcting mutations in EB. However, gene editing approaches are still in the pre-clinical stage and face challenges such as off-target effects and the need for repeated applications. The landscape of EB gene therapies is rapidly expanding, with ongoing and future clinical trials aiming to improve treatment options and potentially cure the disease. Gene editing, particularly CRISPR/Cas9, holds the potential to achieve long-lasting and curative therapies, but further research is needed to address safety and efficacy concerns.Epidermolysis bullosa (EB) is a rare, monogenic skin disease characterized by the formation of extensive blisters and wounds on the skin and mucous membranes due to minimal mechanical stress. The disease is caused by genetic mutations in genes encoding proteins essential for dermal-epidermal connectivity, leading to severe clinical manifestations and reduced life expectancy. Recent breakthroughs in gene therapy have provided promising outcomes for EB patients. Two gene therapeutic approaches are currently showing promise: gene replacement and gene editing. **Gene Replacement:** - **Ex Vivo Gene Therapy:** This approach involves isolating patient skin cells, treating them in vitro to correct the genetic mutation, and then generating autologous skin grafts for transplantation. Successful clinical trials have demonstrated improved wound healing and stable skin integrity in patients with junctional EB (JEB) and recessive dystrophic EB (RDEB). - **In Vivo Gene Therapy:** The first FDA-approved gene therapy for EB, Vyuvek™ (beremagene geperuparc, B-VEC), is a topical treatment for RDEB wounds. It uses a non-replicative herpes simplex virus type 1 vector to deliver full-length collagen type VII (C7) cDNA. Clinical trials showed significant improvements in wound closure and safety, leading to FDA approval. **Gene Editing:** - **CRISPR/Cas9:** This is the most advanced gene editing tool, enabling precise and targeted correction of mutations. CRISPR/Cas9 systems, including base editing (BE) and prime editing (PE), have shown promise in correcting mutations in EB. However, gene editing approaches are still in the pre-clinical stage and face challenges such as off-target effects and the need for repeated applications. The landscape of EB gene therapies is rapidly expanding, with ongoing and future clinical trials aiming to improve treatment options and potentially cure the disease. Gene editing, particularly CRISPR/Cas9, holds the potential to achieve long-lasting and curative therapies, but further research is needed to address safety and efficacy concerns.