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

• 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
• 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

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.

摘要 本研究的目的是开发一种新的预测性体外模型，用于CFTR的个性化反应， 定向治疗本提案响应RFA-HL-15-027（用于预测 对囊性纤维化跨膜传导调节剂的个体反应-指导的治疗）。 囊性纤维化（CF）是一种缩短寿命的遗传性疾病，由囊性纤维化的功能丧失突变引起。 纤维化跨膜电导调节因子（CFTR）基因，编码对离子通道至关重要的阴离子通道 和液体运输。对于某些个体（例如，G551 D杂合子）已被 ivacaftor，一种新的CFTR定向调节剂药物，但对于大多数患者来说， 少得多的实质性。为了改善所有CF患者的生活，至关重要的是体内条件，包括 多种特异性突变和多种药物治疗的复杂性（以及药代动力学相互作用）， 在体外环境中忠实地再现，可用于快速准确地预测药物功效。 我们提出了一个高度新颖的体外个性化预测工具的微流体平台上，利用患者的 我们的治疗策略针对个体复杂的遗传背景， 针对CFTR的药物的生理反应。该模型将在我们的商用 SynVivo®系列基于细胞的检测，将模拟CF肺的复杂气道结构，包括 规模，形态，以及血液，上皮和内皮之间的细胞相互作用。我们将 将其与CFTR功能和气道生理学的新的综合评估相结合，包括多种 在体外环境中通过显微光学相干断层扫描的粘液清除方面， 生物现实主义研究 第一阶段将以明确展示生理反应的微流体平台而告终 在G551 D门控突变的CF患者中观察到。在第二阶段，我们将通过 评估CFTR靶向治疗与多药治疗和详细的临床验证。一个多- 学科，行业和学术合作伙伴关系，在所有领域的专业知识是成功的关键 项目目标的完成已经组装，包括熟练的研究人员研究微流体细胞， 基于分析、CF肺生理学、药物发现和开发、治疗筛选和临床 问题研究最终产品将被商业化的制药公司，药物研究实验室， 从事精确治疗、药物发现和药物递送的大学/非营利中心。的 主要终点是开发一种用作临床工具的测定法，以先验地确定对 CF患者的个性化基础。