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

这个小型企业技术转移（STTR）二期项目的更广泛影响/商业潜力是一种新的药物输送系统，该系统由装载肽的纳米颗粒（NPs）组成，用于靶向和持续释放治疗肽到肠道。该项目产生的药物将是高草酸尿（高尿草酸）、高草酸血症（高血草酸）及相关草酸钙肾结石（COKS）的一流综合治疗药物。数百万患有COKS的患者最终将能够预防这种痛苦和破坏性的疾病，并保持他们的肾脏长期健康。由于单个肾结石增加了肾衰竭的风险，付款人不仅会欣赏每年节省的治疗费用，而且还会欣赏预防慢性肾脏疾病（CKD）和需要永久透析的肾衰竭的经济效益，在美国分别影响约45m和约500k患者。重要的是，它还将影响其他可能受草酸盐影响的疾病的预后，包括CKD及其进展、常染色体显性多囊肾病的囊肿生长进展、肾脏疾病相关心血管疾病和肾移植生存不良。该STTR II期项目旨在开发一种创新药物递送系统的口服途径成分，该系统使用肽负载NPs，用于将新型治疗性肽定位和持续递送到肠粘膜，以解决草酸盐相关疾病。该项目将：(1)开发和表征多种NPs配方。(2)确保携带肽的NPs大部分被输送到小肠和大肠，而不是胃。(3)证实NPs在体外无细胞毒性。(4)证实NPs可显著降低高氧血症和高氧血症小鼠血浆和尿草酸盐水平，而不会引起显著的体内毒性，并且不实现或仅实现极少的全身吸收。(5)通过探索性临床前毒理学研究获得肽负载NP的初步安全性数据。开发的NP制剂中至少有一种应将肽递送到小肠和大肠，在体外无明显的细胞毒性，降低血浆和尿液草酸盐水平，而不会引起显著的体内毒性。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值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 Small Business Technology Transfer (STTR) Phase II project is a novel drug delivery system composed of peptide-loaded nanoparticles (NPs) for targeted and sustained release of therapeutic peptides to the intestine. The drug resulting from this project will be first-in-class comprehensive treatment for hyperoxaluria (high urine oxalate), hyperoxalemia (high blood oxalate), and related calcium oxalate kidney stones (COKS). Millions of patients suffering from COKS will finally be able to prevent this painful and damaging disease and preserve their long-term kidney health. Since a single kidney stone increases the risk of kidney failure, payers will not only appreciate the annual savings on treatment, but also the economic benefits of preventing chronic kidney disease (CKD) and kidney failure requiring permanent dialysis, affecting ~45 M and ~500 K patients in the US, respectively. Importantly, it will also impact the outcome of other disorders potentially affected by oxalate, including CKD and its progression, progression of cyst growth in autosomal dominant polycystic kidney disease, kidney disease-associated cardiovascular diseases, and poor renal transplant survival. This STTR Phase II project aims to develop the oral route component of an innovative drug delivery system using peptide-loaded NPs for localized and sustained delivery of novel therapeutic peptides to the intestinal mucosa to address oxalate-related disorders. This project will: (1) Develop and characterize multiple NPs formulations. (2) Ensure that the peptide-loaded NPs are largely delivered to the small and large intestines, but not to the stomach. (3) Confirm that the NPs have no cellular toxicity in vitro. (4) Confirm that NPs significantly reduce plasma and urinary oxalate levels in hyperoxalemia and hyperoxaluric mice without causing significant in vivo toxicity, and achieving no or minimal systemic absorption. (5) Obtain initial safety data for the peptide-loaded NP via an exploratory preclinical toxicology study. At least one of the developed NP formulations should deliver the peptides to the small and large intestines, present no significant cellular toxicity in vitro, and reduce plasma and urinary oxalate levels without causing significant in vivo toxicity.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.