Topical application of heterologous protein-expressing Staphylococcus epidermidis for potential therapeutic treatment of skin diseases

项目总结

PROJECT SUMMARY Current treatment options for a number of skin diseases generally aim for symptomatic relief and fail to address underlying pathophysiological changes leading to skin disease. In the case of genetic mutations that cause loss of function mutations, supplementation of the missing protein is a viable approach to treatment. However, delivery of functional protein to the target keratinocytes presents a significant challenge; moreover, the cost of protein production and purification creates a significant hurdle to developing a commercially viable treatment. Finally, given the natural turnover rate in the skin, constant reapplication of protein would be needed, which compounds issues related to cost of treatment, adherence, and convenience. Azitra is a preclinical company focused on microbiome-based therapeutics. We are developing a platform that consists of an engineered S. epidermidis that is able to establish residence on human skin and secrete therapeutic protein in situ. An ointment with an inoculum of such bacteria could be infrequently applied to skin, providing constant, low-cost, convenient delivery of therapeutic protein. Natural properties of S. epidermidis also include secretion of antimicrobial peptides against S. aureus and stimulation of regulatory T-cells, making S. epidermidis an ideal secretion platform. The proposed Phase I research plan will focus on proof-of-concept studies to determine the spatio-temporal growth characteristics of our S. epidermidis production and delivery system (Aim 1) and to characterize the spatio-temporal dynamics of sGFP that secreted by S. epidermidis in a skin equivalent model (Aim 2). In the next phase (Phase II) following this STTR Phase I project. The application of this platform will be tested with filaggrin secreted by S. epidermidis in pre- clinical models of atopic dermatitis.