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

这个STTR项目的更广泛的影响/商业潜力是开发一种由多肽水凝胶纳米颗粒组成的新型药物输送系统，用于向肠道定向和持续释放治疗性多肽。胃肠道系统和肠道微生物群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。追求的第一个适应症是高草酸尿和相关的复发性肾结石和肾脏疾病。在美国，草酸钙肾结石(KS)患者超过2700万(男性每5人中就有1人受到影响，女性每11人中就有1人患病)，全球发病率甚至更高，KS是一种没有有效药物的医疗流行病。芝加哥大学最近的发现揭示了通过需要肠道局部作用的新型多肽来治疗高草酸尿症的机会。因此，一种独特的多肽水凝胶纳米给药系统可以为数百万高草酸尿症患者提供一流的治疗。更重要的是，这个药物系统为其他困难的胃肠道疾病打开了更多口服局部给药的多肽疗法的大门，创造了可观的医疗保健和经济收益。这个STTR项目正在开发一种创新的药物输送系统，由多肽水凝胶纳米粒(PLHN)作为载体将新的多肽输送到肠道上皮细胞，最终使一流的口服药丸能够预防和治疗高草酸尿和相关的肾结石(KS)。一旦投放，纳米颗粒将附着在肠道粘膜上，并缓慢释放多肽，刺激肠道草酸分泌，从而降低血浆和尿草酸，从而防止KS的形成。这种传递将使多肽能够立即作用于肠道上皮细胞，诱导草酸分泌，然后被蛋白水解酶降解，模仿肠道细菌的行为，多肽就是从肠道细菌中提取出来的。研究目标为：1.开发PLHN，用于将多肽持续和局部地输送到肠上皮细胞。多肽的释放动力学将被量化，以确保4周的释放持续时间。2.结果表明，经直肠灌肠和灌胃给药的PLHN将以局部/持续的方式将多肽输送到肠上皮细胞，并能显著降低高草酸血症和高草酸尿小鼠的血浆和尿草酸水平。显示每3天给药一次，与每天给药两次相比，同样可以降低尿液和血浆草酸水平，这将证明可持续释放。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.