STTR Phase I: Developing a novel drug delivery system to enable an oral peptide based drug for kidney stones

STTR 第一阶段：开发一种新型药物输送系统，使口服肽药物能够治疗肾结石

• 批准号: 1914232
• 负责人: Altayeb Alshaikh
• 金额: $ 22.5万
• 依托单位: OXALO THERAPEUTICS, INC.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1914232&HistoricalAwards=false
• 关键词: STTR; Phase; Developing; novel; drug

The broader impact/commercial potential of this STTR project is to develop a novel drug delivery system composed of peptide-loaded hydrogel nanoparticles for targeted and sustained therapeutic peptide release to the intestine. The gastrointestinal system and gut microbiome have emerged as critical drivers of human health, offering new opportunities to treat diseases such as food allergies, fungal infections, inflammatory bowel disease, and hyperoxaluria. However, a new class of drug systems are required to target the local biology of these diseases. The first indication pursued is hyperoxaluria and associated recurrent kidney stones and kidney diseases. With over ~27M calcium oxalate kidney stone (KS) patients in the U.S. (affecting 1 in 5 men and 1 in 11 women) and even higher global incidence, KS is a healthcare epidemic with no effective medication. Recent discoveries at the University of Chicago revealed the opportunity to treat hyperoxaluria through novel peptides that require local action in the intestine. Thus, a unique peptide-loaded hydrogel nanoparticle drug delivery system can enable a first-in-class therapeutic for the millions of patients with hyperoxaluria. More importantly, this drug system opens the door for additional orally administered, locally delivered, peptide therapeutics for other difficult gastrointestinal conditions, creating substantial healthcare and economic gains.This STTR project is developing an innovative drug delivery system consisting of peptide-loaded hydrogel nanoparticles (PLHN) as a vehicle to deliver novel peptides to the intestinal epithelium, ultimately enabling a first-in-class oral pill to prevent and treat hyperoxaluria and related kidney stones (KS). Once delivered, the nanoparticles will adhere to the intestinal mucosa and slowly release the peptides, stimulating intestinal oxalate secretion, thereby lowering plasma and urine oxalate and hence preventing KS formation. Such delivery will enable peptides to immediately act on the intestinal epithelium to induce oxalate secretion, before being degraded by proteolytic enzymes, mimicking the behavior of a gut bacteria, from which peptides were derived. Research objectives are: 1. Develop PLHN for sustained and localized delivery of peptides to the intestinal epithelium. Peptide release kinetics will be quantified to ensure a 4-week release duration. 2. Show that the PLHN, given rectally as enemas and orally by gavage, will deliver the peptides to the intestinal epithelium in a localized/sustained manner, and that they will significantly reduce plasma and urine oxalate levels in hyperoxalemic and hyperoxaluric mice. Showing dosing once every 3 days similarly reduces urine and plasma oxalate levels compared to twice daily dosing will demonstrate sustained releasability.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该 STTR 项目更广泛的影响/商业潜力是开发一种由负载肽的水凝胶纳米粒子组成的新型药物递送系统，用于将治疗性肽定向持续释放到肠道。胃肠道系统和肠道微生物组已成为人类健康的关键驱动因素，为治疗食物过敏、真菌感染、炎症性肠病和高草酸尿等疾病提供了新的机会。然而，需要一类新的药物系统来针对这些疾病的局部生物学。第一个适应症是高草酸尿症和相关的复发性肾结石和肾脏疾病。美国有超过 2700 万草酸钙肾结石 (KS) 患者（影响五分之一的男性和十分之一的女性），全球发病率甚至更高，草酸钙肾结石是一种没有有效药物治疗的医疗保健流行病。芝加哥大学最近的发现揭示了通过需要在肠道中发挥局部作用的新型肽来治疗高草酸尿症的机会。因此，独特的负载肽的水凝胶纳米颗粒药物递送系统可以为数百万高草酸尿症患者提供一流的治疗方法。更重要的是，该药物系统为其他困难胃肠道疾病的额外口服、局部递送肽疗法打开了大门，创造了巨大的医疗保健和经济收益。该 STTR 项目正在开发一种创新的药物递送系统，该系统由负载肽的水凝胶纳米颗粒组成（ PLHN）作为向肠上皮输送新型肽的载体，最终使一流的口服药丸能够预防和治疗高草酸尿症和相关肾结石（KS）。一旦递送，纳米颗粒将粘附在肠粘膜上并缓慢释放肽，刺激肠道草酸盐分泌，从而降低血浆和尿液草酸盐，从而防止KS形成。这种递送将使肽能够立即作用于肠上皮，诱导草酸盐分泌，然后被蛋白水解酶降解，模仿肽来源的肠道细菌的行为。研究目标是： 1. 开发 PLHN，将肽持续、局部递送至肠上皮。肽释放动力学将被量化，以确保 4 周的释放持续时间。 2.表明PLHN，通过直肠灌肠和口服强饲法，将以局部/持续的方式将肽递送至肠上皮，并且它们将显着降低高草酸血症和高草酸尿小鼠的血浆和尿液草酸盐水平。与每天两次给药相比，每 3 天给药一次同样可以降低尿液和血浆草酸盐水平，这将证明持续的释放性。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。