A Predictive In Vitro Model for Screening Personalized Responses to CFTR-directed Therapeutics

用于筛选 CFTR 导向治疗的个性化反应的预测体外模型

基本信息

批准号：
9178545
负责人：
BALABHASKAR PRABHAKARPANDIAN
金额：
$ 34.99万
依托单位：
CFD RESEARCH CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9178545
关键词：
Address Affect Air Anions Architecture Area Award Basic Science Biological Assay Biology Blood Cell Communication Cell model Cell physiology Cells Cellular Morphology Cellular Structures Clinical Clinical Research Coculture Techniques Combined Modality Therapy Communities Complex Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Development Devices Disease Drug Delivery Systems Drug Kinetics Endothelial Cells Endothelium Environment Epithelial Epithelial Cells Epithelium Evaluation Family Foundations Frequencies Genetic Goals Health Hereditary Disease Heterozygote Human In Vitro Individual Industry Infection Inflammation Ions Life Liquid substance Longevity Lung Methodology Microfluidic Microchips Microfluidics Modeling Morbidity - disease rate Mucociliary Clearance Mucous body substance Mutation Optical Coherence Tomography Organ Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phase Physiological Physiology Precision therapeutics Property Regimen Regulator Genes Research Research Institute Research Personnel Safety Structure Testing Therapeutic Time Tubular formation United States Universities Validation Viscosity abstracting airway epithelium base clinical efficacy cystic fibrosis patients drug development drug discovery drug efficacy improved in vitro Model in vivo in vivo Model loss of function mutation model development novel personalized medicine personalized screening phase 1 study pre-clinical predictive tools response screening targeted treatment tool treatment response

项目摘要

Abstract The objective of this study is to develop a novel, predictive in vitro model for personalized responses to CFTR- directed therapeutics. This proposal responds to RFA-HL-15-027 (Human Cellular Models for Predicting Individual Responses to Cystic Fibrosis Transmembrane Conductance Regulator- Directed Therapeutics). Cystic fibrosis (CF) is a life-shortening genetic disease caused by loss-of-function mutations of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene that encodes an anion channel critical for ion and fluid transport. Excellent clinical responses for some individuals (e.g., G551D heterozygotes) have been seen with ivacaftor, a new CFTR-directed modulator drug, but for the majority of patients, benefit has been much less substantial. To improve the lives of all CF patients, it is crucial that in vivo conditions, including the variety of specific mutations and complexity of multi-drug therapy (as well as pharmacokinetic interactions) are faithfully reproduced in an in vitro environment that can be used to rapidly and accurately predict drug efficacy. We propose a highly novel in vitro personalized predictive tool on a microfluidics platform, utilizing a patient’s own cells, to target the therapeutic strategy to an individual’s complex genetic background and assess full physiological responses to CFTR-directed drugs. This model will be developed on our commercially available SynVivo® family of cell based assays and will mimic the complex airway structure of the CF lung, including scale, morphology, and cellular interactions between the blood, the epithelium and the endothelium. We will couple this with a novel, integrative assessment of CFTR function and airway physiology including multiple aspects of mucus clearance via micro-optical coherence tomography in an in vitro environment enabling biologically realistic studies. Phase I will culminate with a clear demonstration of the microfluidic platform for physiological responses observed in CF patients with the G551D gating mutation. During Phase II, we will expand the platform by the evaluation of CFTR-targeted therapeutics with multi-agent therapy and detailed clinical validation. A multi- disciplinary, industry-academic partnership with expertise in all areas essential to the successful accomplishment of project goals has been assembled including skilled investigators studying microfluidics cell- based assays, CF lung physiology, drug discovery and development, therapeutic screening and clinical studies. The end-product will be commercialized to pharmaceutical firms, drug research labs and universities/non-profit centers engaged in precision therapeutics, drug discovery, and drug delivery. The primary endpoint is to develop an assay for use as a clinical tool to a priori determine efficacy on a personalized basis for CF patients.

抽象的本研究的目的是开发一种新颖的、预测性的体外模型，用于对 CFTR 进行个性化反应该提案响应 RFA-HL-15-027（人类细胞预测模型）。对囊性纤维化跨膜电导调节器定向治疗的个体反应）。囊性纤维化（CF）是一种由囊性纤维功能丧失突变引起的缩短寿命的遗传性疾病纤维化跨膜电导调节 (CFTR) 基因，编码对离子至关重要的阴离子通道某些个体（例如 G551D 杂合子）具有出色的临床反应。 ivacaftor 是一种新的 CFTR 定向调节剂药物，但对于大多数患者来说，获益已为了改善所有 CF 患者的生活，至关重要的是体内条件，包括多种特定突变和多药治疗的复杂性（以及药代动力学相互作用）在体外环境中忠实再现，可用于快速准确地预测药物疗效。我们在微流体平台上提出了一种高度新颖的体外个性化预测工具，利用患者的自己的细胞，针对个体复杂的遗传背景制定治疗策略并评估全面该模型将在我们的市售药物上开发。 SynVivo® 系列基于细胞的检测将模拟 CF 肺的复杂气道结构，包括血液、上皮和内皮之间的规模、形态和细胞相互作用。将此与 CFTR 功能和气道生理学的新颖综合评估相结合，包括多个在体外环境中通过微光学相干断层扫描清除粘液的各个方面生物学现实研究。第一阶段将通过清晰展示生理反应的微流体平台而达到高潮在第二阶段，我们将通过在具有 G551D 门控突变的 CF 患者中观察到的结果来扩展该平台。通过多药物治疗和详细的临床验证来评估 CFTR 靶向治疗。学科、行业和学术伙伴关系，在所有领域的专业知识对成功至关重要项目目标的实现已经完成，包括研究微流体细胞的熟练研究人员基于检测、CF 肺生理学、药物发现和开发、治疗筛选和临床最终产品将商业化给制药公司、药物研究实验室和从事精准治疗、药物发现和药物输送的大学/非营利中心。主要终点是开发一种检测方法，用作临床工具，以先验确定某项药物的疗效 CF 患者的个性化基础。