Skin probiotics to treat Netherton Syndrome

Project Summary Netherton syndrome (NS) is a genetic disorder of significant severity impacting the skin, hair, and immune system. The condition arises from mutations within the SPINK5 gene, responsible for encoding LEKTI (Lympho-epithelial Kazal-type inhibitor), a serine protease inhibitor. Ordinarily, the skin's exfoliation process is modulated by the balance between these serine proteases and their inhibitors. Mutations in LEKTI lead to elevated serine protease activity, leading to the persistent skin condition associated with NS. Unfortunately, an FDA-approved therapy remains absent for this condition, with management of symptoms primarily relying on antibacterials, emollients, and corticosteroids. Most therapeutic efforts are to develop small molecule inhibitors, but systemic absorption of these long- lasting molecule often results in toxicity. We propose to genetically engineer a harmless bacterium to temporarily populate the skin and deliver LEKTI fragments, that normally have a short half-life, continuously. In our Phase I SBIR, we established the safety and feasibility of our topical application. In this Phase II application, we fully develop our final cell therapy and show efficacy in diseased in vitro and murine models. This data will provide the crux of our pre-IND (Investigational New Drug) meeting with the FDA. Our platform for continuous production of peptide drugs on the skin surface has the potential to revolutionize the treatment of NS.