Bioengineered skin microbiota for cutaneous mitigation of Netherton Syndrome

PROJECT SUMMARY Current treatment options for many skin diseases especially rare diseases fail to address the underlying causative pathophysiologiesIn the case of genetic mutations that cause loss of function mutationssupplementing the missing protein is a viable approach to treatmentHoweverdelivery of functional protein to the target keratinocytes presents a significant challengemoreoverthe cost of protein production and purification creates a significant hurdle to developing a commercially viable treatmentFinallygiven the natural turnover rate in the skinconstant reapplication of protein would be neededwhich compounds issues related to cost of treatmentcomplianceand convenienceAzitra is a preclinical company focused on microbiome based therapeuticsWe are developing a platform that consists of an engineered Staphylococcus epidermidisa common skin species that establishes residence on human skin and secretes therapeutic protein in situA preparation of such bacteria could be infrequently applied to skinproviding constantlow costand convenient delivery inoculum of therapeutic proteinNatural properties of Sepidermidis also include secretion of antimicrobial peptides against disease causing agents like Saureus and stimulation of regulatory T cellsmaking Sepidermidis an ideal secretion platformThis Small Business Innovation and ResearchSBIRproject 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 diseaseNetherton SyndromeImportantlywe will demonstrate that Sepidermidis can secrete functional LETKI proteinthe protein that is missing in patients with Netherton Syndromeand that these bacteria can improve phenotypic severity of the disease in a mouse modelThe small business concernAzitra Incis currently developing preclinical candidate recombinant bacteria for in situ protein delivery for treating skin diseasesThe academic partnerthe Jackson Laboratory for Genomic Medicineis located less than a mile from Azitra and has world class facilities and subject matter expertise to co direct experimentation and key analysesparticularly given its resources and expertise in the skin microbiome and mouse modelsTogetherwe will establish that LETKI secreting skin commensals is a viablenoveland potent drug delivery method for treating Netherton Syndrome by secreting functional proteins in situ for therapeutic benefit PROJECT NARRATIVE Netherton SyndromeNSis a raresevere skin disease with high mortality and few treatment optionsOur proposal aims to develop a new therapeutic for this diseasea microbe based protein delivery system of LEKTIthe missing protein responsible for NS symptomsIn this proof of concept studywe 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 modelthese results would set the foundation for preclinical trials for a rare and severe skin disease with unmet need