STTR Phase I: Re-engineered skin bacteria as a novel topical drug delivery system

This STTR Phase I project aims to establish the viability of a drug delivery platform that employs an engineered strain of Staphylococcus (S.) epidermidis, a common skin commensal bacterium, that can secrete therapeutic proteins of interest for the ultimate goal of treating skin disease. An ointment with an inoculum of such bacteria could be infrequently applied to skin, providing constant, low-cost, convenient delivery of therapeutic protein in situ. This study proposes proof-of-concept studies to demonstrate that an engineered strain of S. epidermidis can serve as a modular, biological drug delivery chassis that can be modified to treat a range of skin conditions, beginning with atopic dermatitis, Netherton Syndrome, and lamellar ichthyosis. These conditions represent significant commercial opportunities spanning both common and rare diseases, and provide validation for a generalized engineered platform of skin bacteria with broad potential applicability to different skin disorders of multifaceted origin, including genetic, inflammatory, and infectious disorders. Validation of the proposed targets provides the crucial data necessary to attract the talent and investment necessary to build an innovative, diversified skin care company. This project is highly innovative because it proposes using commensal skin microbes to secrete and deliver therapeutic proteins or enzymes that are either missing or could be beneficial in treating certain skin diseases. Current treatment options for many skin diseases aim for symptomatic relief and fail to address underlying pathophysiological changes leading to skin disease. Approaches using direct topical supplementation of purified protein are limited by poor subcutaneous localization to sites of need, production and purification costs, and a requirement for constant application. The proposed Phase I research plan will establish for the first time that (1) commensal bacteria can serve as tunable and highly potent drug delivery systems in the skin; (2) skin commensal bacteria can be manipulated to express and export a therapeutic protein of interest; and (3) commensal bacteria engineered to expresses heterologous proteins can colonize skin stably. This project will be executed using both standard molecular biology tools such as cloning and spectrophotometric analysis as well as advanced methods in confocal imaging and synthetic biology. Together, these studies will establish a new paradigm in drug delivery mechanisms for the treatment of skin diseases, which can also be extended to delivery of broad array of agents to promote skin health.