KERATINOCYTE GENE-TRANSFER AND GENE-THERAPY

Gene therapy has moved beyond the pre-clinical stage to the treatment of a variety of inherited and acquired diseases. For such therapy to b e successful, genes must be efficiently delivered to target cells and gene products must be expressed for prolonged periods of time without toxic effects to the host. This may be achieved by means of an in vivo strategy where genes are transferred directly into a host cell, or by means of an ex vivo approach through which cells are removed. culture d, targeted for gene delivery. and grafted back to the host. Several o bstacles continue to delay safe and effective clinical application of gene therapy in a variety of target cells. The limited survival of tra nsplanted cells, transient expression of transferred genes, and diffic ulties in targeting stem cells are technical issues requiring further investigation. Epidermal and oral keratinocytes are potential vehicles for gene therapy. Several features of these tissues can be utilized t o achieve delivery of therapeutic gene products for local or system ic delivery. These qualities include: (1) the presence of stem cells: (2 ) the cell-, strata-, and site-specific regulation of keratinocyte gen e expression: (3) tissue accessibility: and (4) secretory capacity. Su ch features can be exploited by the use of gene therapy strategies to facilitate: (1) identification, enrichment, and targeting of stem cell s to ensure the continued presence of the transferred gene; (2) high-l evel and persistent transgene expression using keratinocyte-specific p romoters; (3) tissue access needed For culture and grafting for ex viv o therapy and direct in vivo gene transfer; (4) secretion of transgene product for local or systemic delivery; and (5) monitoring of genetic ally modified tissue and removal if treatment termination is required. Optimal gene therapy strategies are being tested in a variety of tiss ues to treat dominant and recessive genetic disorders as well as acqui red diseases such as neoplasia and infectious disease. This experience provides a basis for the application of such clinical studies to a sp ectrum of diseases effecting epidermal and oral keratinocytes. Gene th erapy is in an early stage yet holds great promise for its ultimate cl inical application.