SBIR-STTR Award

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.

This SBIR Phase II project aims to develop a novel engineered microbiome as a potential therapeutic for a rare skin disease called Netherton syndrome. Netherton syndrome (NS) is a rare, severe skin disease with high mortality and few treatment options. This proposal aims to develop a new therapeutic for this disease, a microbe-based protein delivery system of LEKTI, the missing protein responsible for NS symptoms. At the end of this project, a candidate live biotherapeutic product candidate (LETKI-secreting strain of S. epidermidis) will be nominated and the Company will have sufficient data with which to proceed into formal preclinical studies and subsequent human testing. This proposed product will have the potential to address thousands of patients in the U.S., and the broader proof-of-principle of this microbe-based technology offers significant potential to treat millions of patients living with skin conditions. This offers significant advances in innovation in addition to broad commercial potential.This project aims to develop a novel therapeutic candidate composed of an engineered strain of S. epidermidis that secretes LEKTI protein to the skin for the treatment of Netherton syndrome (NS). NS is a rare but severe autosomal recessive disease that affects the skin, hair, and immune system. NS is caused by mutations in in the SPINK5 gene encoding the serine protease inhibitor lymphoepithelial Kazal-type related inhibitor (LEKTI), which contains 15 serine protease inhibitory domains. The goal of this Phase II project is to demonstrate a proof-of-concept therapeutic for NS: an engineered commensal microbe that delivers discrete domains of LETKI to the skin. The proposed Phase II research plan will establish critical criteria for nominating a potential live biotherapeutic product (LBP) candidate composed LEKTI-secreting S. epidermidis. This research will perform key activities in preclinical development of an LBP: identify an optimal sequence of LEKTI; develop analytical methods for detecting LEKTI secreted from an engineered strain of S. epidermidis; and develop analytical methods for measuring biodistribution and adsorption of LEKTI secreted by S. epidermidis in a human in vitro model.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.