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ABSTRACT Necrotizing Enterocolitis (NEC) is an inflammatory disease of the intestines that primarily afflicts preterm infants. In severe cases, intestinal tissue necrosis can lead to perforation, sepsis, and death. NEC is estimated to develop in 7% of very low birth weight infants and carries an associated mortality rate of 30-50%, making it one of the leading causes of death in preterm infants. To prevent colonization and infection by opportunistic bacterial pathogens, preterm infants are commonly administered antibiotics. While antibiotics remain effective for reducing NEC-associated infections and improving outcomes, their broad-spectrum effects can disrupt intestinal colonization by protective bacterial species, leave the intestinal tract open to reinfection, and drive antibiotic resistance in opportunistic pathogens. An updated approach to NEC management that leverages protective bacteria to strengthen the developing gut microbiota after antibiotic treatment is well overdue. At Siolta Therapeutics, we are developing STMC-106, a multistrain Live Biotherapeutic Product (LBP) to prevent and treat NEC. Unlike probiotic products, we will develop STMC-106 under an IND to meet the safety, efficacy, and quality standards required for approval as a biologic product by the FDA. We hypothesize that treatment with STMC-106, a rationally designed LBP containing multiple synergistic bacterial strains as active ingredients, will reduce both opportunistic pathogen burden and intestinal inflammation to improve clinical outcomes in NEC. To test this hypothesis, in Specific Aim 1 we will identify combinations of therapeutic candidate bacteria for inclusion in STMC-106 that act synergistically to enhance NEC therapeutic potential in vitro. Candidate consortia that display growth of all active partner strains on human breastmilk through efficient metabolic cross-feeding will be screened to identify two top-performing consortia that inhibit inflammatory signaling and enhance intestinal epithelial barrier function in vitro. In our Specific Aim 2, we will evaluate the in vivo efficacy of two top-performing STMC-106 formulations in a neonatal piglet model of NEC. We will test the efficacy of these two rationally designed bacterial consortia in both a prevention and treatment model design. Efficacy will be evaluated based on the ability of the candidate interventions to reduce intestinal inflammation and tissue necrosis and the burden of opportunistic pathogens in the gut lumen. Our long-term objective is the clinical development and regulatory approval of STMC-106, an LBP designed for preventing and treating NEC in high-risk preterm infants. Successful development of this LBP could save thousands of preterm infants from this deadly illness each year.