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.

抽象的 这项研究的目的是开发一个新颖的预测性体外模型，以针对CFTR-的个性化反应 定向治疗。这种对RFA-HL-15-027的建议响应（用于预测的人类细胞模型） 对囊性纤维化跨膜电导调节剂的个人反应。 囊性纤维化（CF）是由囊性丧失功能突变引起的一种差异遗传疾病 纤维化跨膜电导调节剂（CFTR）基因，该基因编码一个至关重要的阴离子通道 和流体传输。对于某些个体（例如G551D杂合子）的出色临床反应已有 请参阅Ivacaftor，一种新的CFTR指导调节剂药物，但对于大多数患者，益处一直是 少得多。为了改善所有CF患者的生活，至关重要的是，体内疾病，包括 多种特异性突变和多药疗法的复杂性（以及药代动力学相互作用）是 忠实地在体外环境中复制，该环境可用于快速，准确地预测药物效率。 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，并使用患者的 自己的细胞，将治疗策略靶向个人的复杂遗传背景和评估 对CFTR指导药物的生理反应。该模型将在我们的市售中开发 Synvivo®基于细胞的分析系列，并将模仿CF肺的复杂气道结构，包括 血液，上皮和内皮之间的尺度，形态和细胞相互作用。我们将 将此与CFTR功能和气道生理学的新颖，整合评估，包括多个 在体外环境中通过微光相干断层术的粘液清除方面的方面 生物学上现实的研究。 第一阶段将以微流体平台的明确证明进行物理响应，达到高潮 在患有G551D门控突变的CF患者中观察到。在第二阶段，我们将扩展平台 通过多药治疗和详细的临床验证评估CFTR靶向治疗。多 纪律，行业学术伙伴关系在成功的所有领域中具有专业知识 已经组装了项目目标的完成，包括研究微流体细胞的熟练研究人员 基于CF肺部生理学，药物发现和发育，治疗性筛查和临床的测定法 研究。最终产品将商业化到药物农场，药物研究实验室和 从事精确疗法，药物发现和药物提供的大学/非营利中心。这 主要终点是开发一种用作临床工具的测定，以确定对A的有效性 CF患者的个性化基础。