? Orally delivered cyclosporin A (CsA) is an effective treatment that is used in patients with severe psoriasis. The availability of a topical CsA treatment could provide significant benefit to psoriasis patients. An effective topical CsA formulation could mitigate the side effects of this powerful drug, which include nephrotoxicity and hypertension thereby increasing the breadth of the psoriasis patient population base who might benefit from CsA to include those with mild or moderate symptoms. Past attempts to develop a topical CsA treatment have been largely ineffective. The skin is an excellent barrier for most molecules with a molecular weight of more than 500 Da and has been argued that the relatively high molecular weight of CsA (1,200 Da) hinders the transport of the drug across the stratum corneum. Recently, Mitragotri and coworkers have developed novel combinations of penetration enhancers (SCOPE formulations) that are able to greatly improve the permeability of the stratum corneum. SCOPE compositions have been shown to be effective in delivering molecules with molecular weight of up to 5,000 Da, with minimal levels of skin irritation. We propose here to build on these discoveries to develop topical formulations that are effective in treatment of psoriasis using CsA. In Phase I of the proposal a novel high throughput experimentation system will be used to identify substantially non-irritating formulations that are capable of producing a fifty-fold improvement in the amount of CsA that can be delivered to the skin compared to a standard formulation. In Phase II of the project the leading formulations developed in Phase I will be subjected to animal testing and a small-scale human trial. A topical formulation capable of delivering CsA might also find use as a basis for administering this drug for other indications such as, for example, atopic dermatitis. ? ?