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.

摘要 坏死性小肠结肠炎（NEC）是一种肠道炎症性疾病，主要累及 早产儿在严重的情况下，肠组织坏死可导致穿孔、败血症和死亡。 据估计，NEC发生在7%的极低出生体重儿中，并伴有相关的死亡率 发病率为30- 50%，是早产儿死亡的主要原因之一。为了防止殖民化 以及机会性细菌病原体的感染，早产儿通常施用 抗生素虽然抗生素仍然有效地减少NEC相关感染和改善 结果，它们的广谱作用可以破坏保护性细菌物种的肠道定植， 使肠道容易再次感染，并促使机会致病菌产生抗生素耐药性。 NEC管理的最新方法，利用保护性细菌来加强 抗生素治疗后肠道微生物群的发展是早就应该的。在Siolta Therapeutics， STMC-106是一种多菌株活菌制剂，用于预防和治疗NEC。 与益生菌产品不同，我们将在IND下开发STMC-106，以满足安全性，有效性， FDA批准作为生物制品所需的质量标准。我们假设治疗 以STMC-106为活性组分， 成分，将减少机会性病原体负担和肠道炎症，以改善临床 NEC的成果。为了验证这一假设，在具体目标1中，我们将确定治疗性药物的组合。 用于包含在STMC-106中的候选细菌，其协同作用以增强NEC治疗 体外潜力在人母乳中显示所有活性伴侣菌株生长的候选聚生体 通过有效的代谢交叉喂养将筛选，以确定两个表现最好的财团， 抑制炎症信号传导和增强肠上皮屏障功能。对我国所在 目的2，我们将评估两种表现最好的STMC-106制剂在新生儿中的体内功效。 NEC的仔猪模型。我们将测试这两种合理设计的细菌聚生体在两种情况下的功效。 防治模式设计。将根据候选人的能力评估疗效 干预措施，以减少肠道炎症和组织坏死和负担的机会 肠道中的病原体我们的长期目标是临床开发和监管批准 STMC-106是一种LBP，旨在预防和治疗高危早产儿NEC。成功 这种LBP的发展每年可以挽救成千上万的早产儿免于这种致命的疾病。