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

用于预防和治疗坏死性小肠结肠炎的协同多菌株活生物治疗产品

• 批准号: 10761298
• 负责人: Ricardo Valladares
• 金额: $ 30万
• 依托单位: SIOLTA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-14 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10761298
• 关键词: Advanced Development; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Bifidobacterium; Biological Assay; Biological Products; Biological Response Modifier Therapy; Carbohydrates; Cause of Death; Cessation of life; Clinic; Clinical; Culture Media; Development; Etiology; Exclusion; Formulation; Foundations; Growth; Human; Human Milk; In Vitro; Individual; Infant; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Intervention; Intestinal Diseases; Intestines; Invaded; Lactobacillus; Metabolic; Milk; Modeling; Morbidity - disease rate; Necrotizing Enterocolitis; Neonatal; Oligosaccharides; Opportunistic Infections; Outcome; Perforation; Performance; Phase; Pilot Projects; Premature Infant; Prevention; Probiotics; Process; Safety; Sepsis; Signal Transduction; TLR4 gene; Testing; Therapeutic; Update; Very Low Birth Weight Infant; biobank; candidate selection; clinical development; design; efficacy evaluation; efficacy testing; feeding; gastrointestinal system; gut colonization; gut inflammation; gut microbiota; high risk; high risk infant; improved; improved outcome; in vivo; intestinal epithelium; member; microbial; model design; mortality; necrotic tissue; novel; opportunistic pathogen; pathogen; pathogenic bacteria; porcine model; prevent; prophylactic; rational design; screening; therapeutic candidate; vaginal microbiota

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.

抽象的 坏死性小肠结肠炎（NEC）是肠道的一种炎症性疾病，主要遭受困扰 早产婴儿。在严重的情况下，肠组织坏死会导致穿孔，败血症和死亡。 NEC估计会在7％的非常低的出生体重婴儿中发育，并具有相关的死亡率 率为30-50％，使其成为早产儿的主要死亡原因之一。防止定殖 和机会性细菌病原体感染，早产儿通常是给予的 抗生素。尽管抗生素对于减少NEC相关感染和改善仍然有效 结果，它们的广谱作用会破坏保护性细菌物种的肠道定植， 将肠道开放以恢复，并在机会性病原体中驱动抗生素耐药性。 一种更新的NEC管理方法，利用保护性细菌来增强 抗生素治疗后出现肠道菌群逾期。在Siolta Therapeutics，我们是 开发STMC-106，一种多层蛋白酶实时生物治疗产品（LBP），以预防和治疗NEC。 与益生菌产品不同，我们将在IND下开发STMC-106，以达到安全性，功效和 FDA批准为生物产品所需的质量标准。我们假设这种治疗 与STMC-106（一个合理设计的LBP），其中包含多种协同细菌菌株作为活性 成分，将减轻机会性病原体负担和肠炎以改善临床 NEC的结果。为了检验这一假设，在特定目标1中，我们将确定治疗的组合 候选细菌包含在STMC-106中，以协同作用以增强NEC治疗 体外潜力。候选财团，显示所有活性伴侣菌株在人类母乳中的增长 通过有效的代谢交叉喂养将筛选，以识别两个表现最好的财团 抑制炎症信号传导并增强体外肠上皮屏障功能。在我们的具体情况下 AIM 2，我们将评估新生儿中两个表现最佳的STMC-106配方的体内功效 NEC的仔猪模型。我们将测试这两个合理设计的细菌联盟的功效 预防和治疗模型设计。将根据候选人的能力评估功效 减少肠道炎症和组织坏死的干预措施以及机会主义的负担 肠腔中的病原体。我们的长期目标是临床开发和监管批准 STMC-106的LBP，旨在预防和治疗高风险早产儿的NEC。成功的 这种LBP的发展可以每年从这种致命的疾病中节省数千名早产儿。