Developing a peptide-based oral drug to prevent kidney stones

开发一种基于肽的口服药物来预防肾结石

• 批准号: 10001500
• 负责人: Donna Arvans
• 金额: $ 100万
• 依托单位: OXALO THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001500
• 关键词: Address; Affect; Amino Acids; Biological; Biological Products; Blood; Caco-2 Cells; Calcium Oxalate; Cells; Chicago; Chronic Kidney Failure; Conditioned Culture Media; Crystallization; Development; Diet; Disease; Drug Kinetics; Drug Targeting; Emergency department visit; End stage renal failure; Enteral; Excretory function; FDA approved; Family; Feces; Genetic Diseases; Goals; Health Care Costs; Human; Hyperoxaluria; Intervention; Intestines; Kidney Calculi; Lead; Liver; Medical Care Costs; Modeling; Modification; Mus; Oral; Oral Administration; Organoids; Outcome; Oxalates; Oxalobacter formigenes; Pain; Patients; Peptides; Pharmaceutical Preparations; Phase; Physiological; Plasma; Primary Hyperoxaluria; Protein Binding Domain; Proteins; Rattus; Rectal Administration; Recurrence; Risk; Risk Factors; Series; Sigmoid colon; Signal Pathway; Signaling Protein; Small Business Technology Transfer Research; Source; Structure; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Toxicology; Translational Research; Universities; Urine; Woman; base; capsule; commercialization; design; drug development; gut bacteria; ileum; in vivo; intestinal epithelium; lead optimization; men; mouse model; nonhuman primate; novel; novel therapeutics; pill; pre-clinical; prevent; protein protein interaction; response; success; targeted treatment; urinary

Project Summary/Abstract Kidney stones (KS) are highly prevalent, excruciating, and associated with long term complications of chronic kidney disease (CKD) and end stage renal disease (ESRD). They account for 1.3M ER visits and >$10B of medical costs annually and have a striking recurrence rate of 50% in 5 years and up to 80% in 10 years, reflecting the inadequacies of current interventions. 70-80% of KS are composed of calcium oxalate and small increases in urine oxalate significantly enhance the risk for stone development. Reducing urine oxalate levels results in a lower CaOx supersaturation and decreased KS recurrence. No approved drugs can specifically reduce urine oxalate. The gut bacterium Oxalobacter formigenes (Of) induces colonic oxalate secretion and reduces urinary oxalate excretion via an unknown secretagogue. Use of Of as a therapeutic agent remains problematic given difficulties with recolonization, underscoring the need to identify the factors inducing colonic oxalate secretion. Oxalo Therapeutics has shown that Of-derived factors, by itself, significantly reduced urinary oxalate in hyperoxaluric mice by >32.5% and identified a family of signaling proteins as the major Of-derived factors. These proteins and a series of identified peptides also significantly stimulated oxalate transport by C2 cells. Importantly several peptides also similarly stimulated oxalate transport by human organoids (an ex vivo intestinal epithelium model fully mimicking the gut), underscoring the human relevance. Through this STTR Fast-track proposal, Oxalo Therapeutics aims to develop an oral drug based on these peptides to prevent KS by lowering oxalate in the urine and blood. Specific aims for Phase I: 1. Optimize lead peptides for stability using structural modifications, 2. Evaluate the therapeutic effects of the optimized peptides in primary hyperoxaluria (PH1) mouse model. Optimized peptide(s) that significantly reduce urine & plasma oxalate levels will be taken to Phase II. Specific aims for Phase II, 1. Develop novel peptides (NP) based on modeling of the identified crystal structures, 2. Evaluate the effects of the optimized peptides or NPs in reducing urine & plasma oxalate levels in PH1 mice and enteric (secondary) hyperoxaluria mice, 3. Develop enteric coated capsules containing best performing peptides for oral administration and evaluate effects on the above mice. 4. Perform preclinical toxicology and pharmacokinetics studies in rats and nonhuman primates. Since ~ 50% of urine oxalate is derived from diet and ~50% comes from the liver, the Oxalo product has a mechanistic advantage over competitors by addressing both sources (by extracting oxalate from blood and enhancing its intestinal excretion). Competitors are developing drugs that only target either dietary oxalate or liver oxalate. By lowering plasma oxalate levels, there are also therapeutic implications for hyperoxalemia seen in ESRD, & CKD, and the genetic disease primary hyperoxaluria (PH). This drug can immediately help ~2.7M patients in the US suffering from recurrent KS as a result of hyperoxaluria, representing a ~$3.8B initial market. Oxalo will focus initial efforts on critical translational research and early drug development milestones.

项目摘要/摘要 肾结石(KS)非常普遍，令人痛苦，并与慢性肾脏病的长期并发症有关。 肾病(CKD)和终末期肾病(ESRD)。他们的急诊室访问量达到130万次，价值100亿美元 每年的医疗费用，5年内复发率高达50%，10年内复发率高达80%，这反映了 当前干预措施的不足之处。70%-80%的KS由草酸钙和小量增加组成 尿液中的草酸盐会显著增加结石形成的风险。降低尿草酸水平会导致 降低CaOx过饱和度，减少KS复发。没有批准的药物可以特别减少尿量 草酸盐。肠道细菌草酸杆菌(OF)诱导结肠草酸分泌，减少尿量 通过一种未知的促分泌剂排泄草酸。将作为治疗剂的使用仍然存在问题 他强调了重新定植的困难，强调需要查明引起结肠草酸分泌的因素。 Oxalo Treateutics已经表明，衍生因子本身显著减少了尿草酸 高草酸尿症小鼠减少了32.5%，并确定一个信号蛋白家族是主要的衍生因子。这些 蛋白质和一系列已鉴定的多肽也显著刺激C2细胞的草酸转运。重要的是 几种多肽也类似地刺激类器官(一种体外肠道上皮)对草酸的运输 完全模仿肠道的模型)，强调与人类的相关性。通过这项STTR快速通道提案， Oxalo Treateutics的目标是开发一种基于这些肽的口服药物，通过降低体内草酸来预防KS 尿液和血液。第一阶段的具体目标：1.利用结构优化铅多肽的稳定性 改良，2.评价优化多肽对原发性高草酸尿症(PH1)小鼠的治疗效果 模特。显著降低尿草酸和血浆草酸水平的优化肽(S)将进入第二阶段。 第二阶段的具体目标：1.基于已鉴定晶体结构的模型开发新的多肽(NP)， 2.评价优化的多肽或NPs对PH1小鼠尿草酸和血浆草酸水平的影响 和肠道(继发性)高草酸尿小鼠，3.研制性能最好的肠溶胶囊 口服多肽并评价其对上述小鼠的作用。4.进行临床前毒理学和 大鼠和非人灵长类动物的药代动力学研究。由于约50%的尿草酸来自饮食和 ~50%来自肝脏，Oxalo产品通过以下方式比竞争对手具有机械优势 这两个来源(通过从血液中提取草酸盐并增加其肠道排泄)。竞争对手是 开发只针对膳食草酸或肝脏草酸的药物。通过降低血浆草酸水平， 对ESRD、CKD和遗传性疾病的高草酸血症也有治疗意义 高草酸尿症(PH)。这种药物可以立即帮助美国约270万名复发的KS患者 高草酸尿症的结果，代表了约38亿美元的初始市场。Oxalo将最初的工作重点放在关键的翻译上 研究和早期药物开发的里程碑。