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

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.