Topical Cyclosporin A for Dermatitis and Psoriasis

DESCRIPTION: (Verbatim) The protective outer layer of the skin, the stratum corneum, serves to exclude therapeutic drugs like cyclosporin A (CsA). Preliminary experiments have unambiguously established that short polymers of arginine cross the stratum corneum of murine and human skin to enter the epidermal and dermal tissue. Similar penetration into all layers of the skin was observed when short polymers of arginine were conjugated to CsA, which in unconjugated form fails to penetrate skin. These conjugates reached infiltrating T cells in the dermis of inflamed skin. Related conjugates using a releasable linker provided therapeutically active CsA conjugates, thus providing a means of focally delivering systemically toxic drugs for the treatment of psoriasis and dermatitis while alleviating the problem of systemic toxicity. The goal of this proposal is to select a lead CsA -transporter conjugate for further development. This will entail the synthesis and evaluation of a series of GsA-transporter conjugates comprising a set of transporters with a range of tissue penetrating ability. A labeled subset will be assessed for tissue penetration and a corresponding releasable subset will be evaluated in vitro by assaying their ability to inhibit secretion of Il-2 by activated T cells and in vivo using an animal model of contact dermatitis. PROPOSED COMMERCIAL APPLICATION: Current topical therapies for dermatitis and psoriasis all have fundamental problems. When administered orally, immunosuppressants can be effective, and by, intralesional injection, CsA dramatically reduces or clears psoriatic lesions. CsA is not currently used to treat dermatitis and is used only in severe cases of psoriasis because of systemic toxicity. The proposed conjugates are expected to provide the first highly efficacious topical treatments for atopic/contact dermatitis and psoriasis, which together total >20 million US patients.