Cutaneous gene transfer and therapy: the present and the future

The easy accessibility of the skin as a therapeutic target provides an exci ting potential for this organ for the development of gene therapy protocols for cutaneous diseases and a variety of metabolic disorders. Thus far, ful l phenotypic reversion of a diseased phenotype has been achieved in vivo fo r junctional epidermolysis bullosa and X-linked or lamellar ichthyosis and in vitro for xeroderma pigmentosum. These recessive skin diseases are chara cterized by skin blistering, abnormalities in epidermal differentiation and increased development of skin cancers, respectively. Corrective gene deliv ery at both molecular and functional levels was achieved by transduction of cultured skin cells using retroviral vectors carrying the specific curativ e cDNA. These positive results should prompt clinical trials based on trans plantation of artificial epithelia reconstructed ex vivo using genetically modified keratinocytes. Promising results have also been obtained in phenot ypic reversion of cells isolated from patients suffering from a number of m etabolic diseases such as gyrate atrophy, familial hypercholesterolemia or phenylketonuria. In these diseases transplantation of autologous artificial epithelia expressing the transgenes of interest or direct transfer of the DNA to the skin represents a potential therapeutic approach for the systemi c delivery of active molecules. Successful cutaneous gene therapy trials, h owever, require development of protocols for efficient gene transfer to epi dermal stem cells, and information about the host immune response to the re combinant polypeptides produced by the implanted keratinocytes. The availab ility of spontaneous animal models for genodermatoses will validate the gen e therapy approach in preclinical trials. Copyright (C) 2000 John Wiley & S ons, Ltd.