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

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 and to characterize the spatio temporal dynamics of sGFP that secreted by S epidermidis in a skin equivalent model Aim 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 PROJECT NARRATIVE The proposal aims to establish proof of concept that a platform can be developed that consists of an engineered commensal skin bacterial species that is able to establish residence on a skin model and secretes a desired protein that can penetrate the stratum corneum The small business partner Azitra Inc is currently developing preclinical candidates using bacterial systems for in situ protein delivery for treating skin diseases The academic partner Yale University has world class facilities and subject matter expertise to co direct experimentation and key analyses Together we are aiming to test if this platform is a viable approach as a therapeutic for treating a range of skin diseases by simultaneously modulating the skin microbiome and secreting proteins in situ for therapeutic benefit