This proposal is part of a program to develop gene medicines for treatment of dermatoses such as psoriasis utilizing a novel DNA expression vector (HK1) capable of directing high-level tissue-specific expression from keratinocytes in the epidermis. The HK1 vector contains transcription and translation control elements derived from the human K1 gene. In transgenic animals, this vector directs high levels of gene expression specifically in proliferative basal cells, as well as differentiated supra-basal cells of the epidermis. Phase-I studies will focus on demonstrating the feasibility of expressing therapeutic products in normal and hyperplastic skin after direct administration of the HK1 vector into the epidermis by particle bombardment. We will study expression of a marker gene beta-galactosidase as well as TGF-beta, a growth regulating factor which may be useful in inhibiting hyperproliferation in diseases such as psoriasis. We will study gene expression in normal mice and in the transgenic HK-1-TGF-alpha mouse where genetically engineered overexpression of TGF-alpha induces thickening, hyperproliferation, and hyperkeratosis of the skin similar to that seen in psoriasis. Phase-II studies will focus on developing novel, methods for gene delivery to skin, expression in human epidermal models, and the development of new gene medicines for treating the hyperproliferation and inflammation characteristic of psoriasis.
