A Synergistic Multistrain Live Biotherapeutic Product for the Prevention and Treatment of Necrotizing Enterocolitis

摘要 坏死性小肠结肠炎(NEC)是一种主要影响肠道的炎症性疾病。 早产儿。严重时，肠组织坏死可导致穿孔、败血症和死亡。 据估计，7%的极低出生体重儿会发生NEC，并伴随着相关的死亡 30-50%的发病率，使其成为早产儿死亡的主要原因之一。为了防止殖民 和机会细菌病原体的感染，早产儿通常会接受治疗 抗生素。虽然抗生素仍然有效地减少NEC相关感染并改善 结果，它们的广谱效应可以通过保护性细菌物种扰乱肠道定植， 使肠道容易再次感染，并促使机会性病原体产生抗生素耐药性。 NEC管理的最新方法，利用保护性细菌来加强 在抗生素治疗后发展肠道微生物区系早就应该了。在西奥塔治疗公司，我们 开发预防和治疗NEC的多菌株活生物治疗产品STMC-106。 与益生菌产品不同，我们将在IND下开发STMC-106，以满足安全性、有效性和 FDA批准为生物制品所需的质量标准。我们假设这种治疗 在STMC-106的作用下，设计合理的含有多个协同菌株的LBP具有活性 成分，将减少机会致病菌负担和肠道炎症，以改善临床 NEC的结果。为了检验这一假设，在特定目标1中，我们将确定治疗方法的组合 STMC-106中协同增强NEC治疗作用的候选细菌 在体外有潜力。在母乳上显示所有活跃的伙伴菌株生长的候选财团 通过高效的代谢交叉喂养，将筛选出两个表现最好的财团， 抑制炎性信号转导，增强肠上皮屏障功能。在我们的特定情况下 目的2，我们将评估两种最有效的STMC-106制剂在新生儿中的体内疗效 NEC的仔猪模型。我们将测试这两种合理设计的细菌联合体在这两种情况下的效果 一种防治模式的设计。疗效将根据候选人的能力进行评估 减少肠道炎症和组织坏死以及机会性疾病负担的干预措施 肠腔里有病原体。我们的长期目标是临床开发和监管批准 STMC-106，一种旨在预防和治疗高危早产儿NEC的LBP。成功 这种LBP的发展每年可以挽救数以千计的早产儿免于这种致命的疾病。

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.