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.
Project Terms: Address; Affect; antimicrobial peptide; Area; Asthma; Bacteria; Bacterial Proteins; base; Biochemical; Biological Assay; Biomedical Engineering; Birth; Businesses; Calcineurin inhibitor; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; commensal bacteria; commensal microbes; Complement; Compliance behavior; corticosteroid inhibitor; cost; CRISPR/Cas technology; Cutaneous; Development; Disease; disease phenotype; DNA Sequence Alteration; Drug Delivery Systems; Embryo; Engineered Probiotics; Engineering; experimental study; Foundations; Functional disorder; Genes; Genomic medicine; Goals; Hair; Hair shaft structure; Histologic; Human; Hypersensitivity; IgE; Immune system; Immunologic Deficiency Syndromes; immunoregulation; improved; In Situ; In Vitro; in vitro activity; in vitro Assay; in vitro testing; indexing; Infant; Infection; inhibitor/antagonist; innovation; interest; Intravenous Immunoglobulins; keratinocyte; Kininogenase; Laboratories; Lesion; Life; loss of function mutation; Measures; Methods; Microbe; microbiome; microbiome therapeutics; Modeling; Morphology; mortality; mouse model; Mus; Mutation; Neonatal; novel; novel strategies; novel therapeutics; outcome forecast; pathogen; Patients; Peptide Hydrolases; Phenotype; Plasmids; pre-clinical; Pre-Clinical Model; preclinical trial; Preparation; Production; Property; Proteins; Protocols documentation; Rare Diseases; Reapplication; Recombinants; Recurrence; Regulatory T-Lymphocyte; Reporting; Research Project Grants; residence; Resources; Serine Protease; Serine Proteinase Inhibitors; Severities; Severity of illness; Skin; skin disorder; skin microbiome; skin microbiota; Small Business Innovation Research Grant; Staphylococcus aureus; Staphylococcus epidermidis; Symptoms; Syndrome; System; Testing; The Jackson Laboratory; Therapeutic; therapeutic protein; Time; Topical application; Topical Corticosteroids; Treatment Cost; Treatment Efficacy;
