Current treatment options for many skin diseases?especially rare diseases?fail to address the underlying causative pathophysiologies. In the case of genetic mutations that cause loss of function mutations, supplementing 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, compliance, and convenience. Azitra is a preclinical company focused on microbiome-based therapeutics. We are developing a platform that consists of an engineered Staphylococcus epidermidis, a common skin species that establishes residence on human skin and secretes therapeutic protein in situ. A preparation of such bacteria could be infrequently applied to skin, providing constant, low-cost, and convenient delivery inoculum of therapeutic protein. Natural properties of S. epidermidis also include secretion of antimicrobial peptides against disease-causing agents like S. aureus and stimulation of regulatory T-cells, making S. epidermidis an ideal secretion platform. This Small Business Innovation and Research (SBIR) project aims to establish proof-of-concept development of an iteration of our drug delivery platform consisting of engineered commensal skin bacterial species for the potential treatment of a rare and severe skin disease, Netherton Syndrome. Importantly, we will demonstrate that S. epidermidis can secrete functional LETKI protein (the protein that is missing in patients with Netherton Syndrome) and that these bacteria can improve phenotypic severity of the disease in a mouse model. The small business concern, Azitra Inc., is currently developing preclinical candidate recombinant bacteria for in situ protein delivery for treating skin diseases. The academic partner, the Jackson Laboratory for Genomic Medicine, is located less than a mile from Azitra and has world-class facilities and subject matter expertise to co-direct experimentation and key analyses, particularly given its resources and expertise in the skin microbiome and mouse models. Together, we will establish that LETKI-secreting skin commensals is a viable, novel, and potent drug delivery method for treating Netherton Syndrome by secreting functional proteins in situ for therapeutic benefit.
Netherton Syndrome (NS), is a rare, severe skin disease with high mortality and few treatment options. Our 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. In this proof-of-concept study, we will create a new mouse model for NS and evaluate if the topical application of an engineered Staphylococcus epidermidis that secretes LEKTI can resolve the severe skin and atopic symptoms in a preclinical model; these results would set the foundation for preclinical trials for a rare and severe skin disease with unmet need.
