Advances in molecular genetics make it plausible to correct heritable disorders of malformation and morphogenesis of skin, as well as other heritable disorders. The genesis of this program project lies in the need to determine the potential and the limitations of correcting heritable disorders by transfecting non-defective copies of genes into somatic cells (somatic cell gene therapy) of an individual expressing a disease because of a defective gene(s). For this the following are needed: a. Systems to assess expression of human genes in a human organ (skin) that could be readily translated to the clinical setting. b. Expertise for maximizing transfection of and expression by such genes in cells of the skin. c. A thorough understanding of factors that define tissue levels of the transfected gene product. d. Rodent models of heritable diseases that are potentially correctable by somatic cell gene therapy using cells of the skin. This program project brings these elements to focus on the potential and limitations of using genetically modified skin to correct either malformations, abnormalities of morphogenesis, or heritable disorders characterized by specific plasma protein deficiencies. Prior to clinical use five critical questions need to be answered. 1. Can genetically modified skin be transplanted in ways that have clinical applicability? 2. What are the limitations of production of gene products by genetically modified skin, i.e. what types of disorders can be corrected? 3. Which cellular components of skin most effectively carry the gene needed to correct the disorder? 4. Does genetically modified skin function as normal skin? 5. Can this technology be used to correct relevant models of heritable disease? Three Projects and 2 Cores define the approach. Project 0001: Development and assessment of approaches for using genetically modified skin cells. Project 0002: Definition of parameters which regulate tissue levels by transfected genes. Project 0003: Use of genetically modified skin cells to correct murine models of human disease. Core 9001 = cell culture; Core 9002 = molecular biology, gene transfection.
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