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.
Public Health Relevance Statement: 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.
Project Terms: Address; Anti-Inflammatory Agents; Antibiotics; antimicrobial peptide; Atopic Dermatitis; Bacteria; Bacterial Proteins; base; Biological Assay; Biological Models; Businesses; Calcineurin inhibitor; Cells; Characteristics; Chronic; Confocal Microscopy; cost; Coupled; Data; Defect; Dermal; Development; Disease; DNA Sequence Alteration; Ecology; Engineering; Epidermis; Experimental Designs; expression vector; filaggrin; Gene Mutation; Genes; Genetic; Genetic Skin Diseases; Grant; Growth; Health Care Costs; Histology; Human; Ichthyosis Vulgaris; Image; imaging system; Immunohistochemistry; In Situ; In Vitro; in vitro Model; Inflammatory; interest; keratinocyte; Location; loss of function mutation; Measures; microbial; microbiome; Modeling; Mutation; novel strategies; Ointments; Patients; Penetration; Peptides; Phase; Physiology; Population; pre-clinical; Pre-Clinical Model; Predisposition; Production; Property; Protein Export Pathway; Proteins; Reapplication; Recombinants; Regulatory T-Lymphocyte; Research; residence; Resolution; Role; Signal Transduction; Skin; skin barrier; skin disorder; skin microbiome; Small Business Technology Transfer Research; Staging; Staphylococcus aureus; Staphylococcus epidermidis; Stratum corneum; Structure; Supplementation; System; Testing; Therapeutic; therapeutic protein; Therapeutic Uses; Time; Topical application; Topical Corticosteroids; treatment adherence; Universities
