SBIR Phase I: Improving in vitro prediction of oral drug permeability and metabolism using a novel 3D canine organoid model

SBIR 第一阶段：使用新型 3D 犬类器官模型改进口服药物渗透性和代谢的体外预测

• 批准号: 1912948
• 负责人: Kimberly Dao
• 金额: $ 22.5万
• 依托单位: 3D HEALTH SOLUTIONS, 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 2021-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1912948&HistoricalAwards=false
• 关键词: SBIR; Phase; Improving; vitro; prediction

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I Project is to provide the pharmaceutical industry with improved pre-clinical screening assay for oral drug absorption. Current in vitro methods for characterizing gastrointestinal absorption are based on unreliable assays, with 90% of all drugs developed ultimately failing to enter the market. Practically, these limitations delay the development of critically needed therapeutic drugs and dramatically increase drug prices and health care costs. There is, therefore, a critical need to develop more predictive in vitro testing assays that will allow for early selection of the most promising drug candidates to reduce the number of live animal studies and their associated costs, while accelerating transition from pre-clinical research to early drug development. The technology is based on the discovery, fundamental characterization and bioarchiving of adult canine intestinal stem cell lines, called 3-dimensional (3D) canine intestinal organoids. These miniguts emulate the physiology of the functional intestine much more closely than currently available methods and have the potential to provide superior drug screening over currently used assays. This SBIR Phase I is a proposal to establish that in vitro predictability of oral drug absorption can be improved using canine intestinal organoids vs. standard 2D in vitro assays, such as Caco2 and MDCK cell lines. In Aim 1, the goal is to determine intestinal absorption and permeability of therapeutic drugs as a function of disease and intestinal segment as compared with conventional in vitro models. This will be achieved by quantifying passive and active permeability of drugs, as well as drug transporter expression and function in 3D canine organoids vs. conventional cell systems. In Aim 2, the goal is to determine intestinal metabolism of therapeutic drugs as a function of disease and intestinal segment in canine organoids compared to standard in vitro models. Ultimately, quantitative data generated through these experiments will be imported into a commercial software to simulate the disposition kinetics of a predefined set of candidate drugs. Performances of the model predictions will be evaluated by comparing simulated vs. observed drug kinetic plasma data from the literature for validation purposes.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.

这个小型企业创新研究(SBIR)第一阶段项目的更广泛的影响/商业潜力是为制药业提供改进的口服药物吸收的临床前筛选试验。目前用于表征胃肠道吸收的体外方法是基于不可靠的检测方法，所有研发的药物中有90%最终未能进入市场。实际上，这些限制推迟了急需的治疗药物的开发，并极大地提高了药品价格和医疗保健成本。因此，迫切需要开发更具预测性的体外测试分析，以便及早选择最有希望的候选药物，以减少活体动物研究的数量及其相关成本，同时加快从临床前研究向早期药物开发的过渡。这项技术是基于成年犬肠道干细胞系的发现、基本特征和生物归档，称为三维(3D)犬肠道器官。这些微管模拟了功能肠道的生理学，比目前可用的方法更接近，并有可能提供比目前使用的分析更好的药物筛选。这项SBIR第一阶段是一项建议，旨在建立使用犬肠道有机化合物与标准的2D体外分析方法(如Caco 2和MDCK细胞系)相比，可以提高口服药物吸收的体外预测性。在目标1中，目标是与传统的体外模型相比，确定治疗药物的肠道吸收和渗透性作为疾病和肠段的函数。这将通过量化药物的被动和主动渗透性，以及药物转运体在3D犬类器官与传统细胞系统中的表达和功能来实现。在目标2中，目标是与标准的体外模型相比，确定治疗药物在犬类器官中的肠道代谢作为疾病和肠段的功能。最终，通过这些实验产生的定量数据将被导入商业软件，以模拟一组预定义的候选药物的处置动力学。模型预测的性能将通过比较模拟和观察到的药物动力学血浆数据进行评估，以进行验证。该奖项反映了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。