Recent progress in molecular genetics has identified genes responsible for a wide variety of inherited skin disorders such as, the potentially life-threatening sub-types junctional epidermolysis bullosa (JEB). This new knowledge, however, has not yet been translated into useful therapies. Because proteins defective in JEB are large and contain multiple functional domains, successful treatment with conventional pharmacological approaches is unlikely. In light of this, we have focused our efforts on gene therapy. We have achieved genetic correction of human genetic skin disease tissue in vivo. However, due to loss of transgene expression over time, this correction could not be sustained beyond 4 weeks. Recently, using modified retroviral vectors, we have achieved sustained marker gene expression in human skin tissue in vivo. The goal of this project is to apply this new capability to achieve durable corrective gene delivery of the laminin 5-beta3 (LAM5-beta3) gene in our human JEB tissue/SCID mouse model as a springboard for initiating gene therapy trials in humans.