Developing a peptide-based oral drug to prevent kidney stones

项目概要/摘要 肾结石（KS）是高度流行的、痛苦的，并且与慢性肾功能衰竭的长期并发症相关。 肾病（CKD）和终末期肾病（ESRD）。他们占130万ER访问和> 100亿美元的 每年的医疗费用，5年内复发率高达50%，10年内高达80%，反映了 当前干预措施的不足。70 - 80%的KS由草酸钙组成， 尿中草酸盐显著增加结石形成的风险。降低尿草酸盐水平导致 降低CaOx过饱和度和降低KS复发率。没有批准的药物可以专门减少尿液 草酸盐。肠道细菌产草酸杆菌（Oxalactiniformigenes，Of）诱导结肠草酸分泌， 通过未知的促分泌素排泄草酸盐。使用Of作为治疗剂仍然存在问题， 结肠草酸盐化的困难，强调需要确定诱导结肠草酸盐分泌的因素。 Oxalo Therapeutics已经表明，Of-derived因子本身显著减少了尿草酸盐， 高尿酸小鼠中，通过> 32.5%，并确定了一个家族的信号蛋白作为主要的Of-衍生因子。这些 蛋白质和一系列鉴定的肽也显著刺激C2细胞的草酸盐转运。重要的 几种肽也类似地刺激人类器官（离体肠上皮）的草酸盐转运 模型完全模仿肠道），强调了人类的相关性。通过这项STTR快速通道提案， Oxalo Therapeutics旨在开发一种基于这些肽的口服药物，通过降低体内草酸盐来预防KS。 尿液和血液。第一阶段的具体目标：1.使用结构优化先导肽的稳定性 修改，2.评价优化的肽在原发性高尿酸（PH 1）小鼠中的治疗效果 模型显著降低尿液和血浆草酸盐水平的优化肽将进入II期。 第二阶段的具体目标，1。基于已鉴定晶体结构的建模开发新型肽（NP）， 2.评价优化的肽或NP在降低PH 1小鼠的尿和血浆草酸盐水平中的作用 和肠（继发性）高尿酸小鼠，3.开发性能最佳的肠溶胶囊 用于口服给药的肽，并评价对上述小鼠的作用。4.进行临床前毒理学研究， 在大鼠和非人灵长类动物中的药代动力学研究。由于约50%的尿草酸盐来自饮食， 约50%来自肝脏，Oxalo产品通过解决 两种来源（通过从血液中提取草酸盐并增强其肠道排泄）。竞争对手是 开发只针对饮食草酸盐或肝脏草酸盐的药物。通过降低血浆草酸水平， 也可用于治疗ESRD、CKD和原发性遗传性疾病中的高脂血症。 高尿酸血症（PH）。这种药物可以立即帮助美国约270万患有复发性KS的患者， 高尿酸血症的结果，代表了约38亿美元的初始市场。Oxalo将把最初的努力集中在关键的翻译上 研究和早期药物开发里程碑。

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.