The approval of the cystic fibrosis (CF) drug invocator for patients with the G551D mutation validates CFTR modulators for improving clinical outcomes in CF. For most CF patients (with F508del and other mutations), however, multi-drug combination therapy will likely be necessary, and sensitive biomarkers of augmented CFTR function in response to various agents will be needed. In vivo assays employed to date have not been predictive of efficacy; neither do they correlate well with individual patient improvement. The proposed project combines two recent advances by researchers at the University of Alabama at Birmingham (UAB) and the Massachusetts General Hospital (MGH) to produce a novel in vitro human cell biomarker that will predict CFTR function in individual patients: 1) methods which allow primary human epithelial cell cultures of nasal origin (HNE) to proliferate rapidly and to maintain an airway phenotype; and 2) a pioneer imaging technology (Micro- Optical Coherence Tomography [OCT]) which permits simultaneous and co-localized quantification of multiple elements of airway function, including mucociliary transport, demonstrating reproducible anatomic differences between CF and normal human explants and functionally characterizing in situ fully-differentiated primary human bronchial epithelial cells (HBE) grown in culture. OCT can also directly visualize dynamic differences between CF and wild-type tissues, simultaneously measuring collapsed airway surface liquid (ASL) height, reduced cilia beat frequency (CBF), delayed mucus transport (MCT), and increased mucus viscosity. Preclinical data indicate primary human airway cell cultures strongly predict ion transport efficacy of CFTR potentiators and correctors on a group wise basis. Progenra will work with UAB and MGH to develop and commercialize the novel HNE culture as an in vitro biomarker for CFTR function, employing OCT for simultaneous detection of the markers. In Phase 1 the validity and utility of combining primary nasal cells with optimized and automated ?OCT-based analysis of the functional microanatomy will be established as a tool to predict efficacy in individual patients. It will first be demonstrated that an automated ?OCT imaging acquisition and analysis system can distinguish the functional microanatomy (i.e. ASL/PCL depth, CBF, MCT, and viscosity) of normal and CF differentiated HNE. It will then be ascertained whether HNE cells from twenty-five (25) G551D CF subjects enrolled in the GOAL study, an open-label observational trial of invocator, predict therapeutic response to invocator on an individual basis. In Phase II, the study will be expanded to ~200 patients and five different mutant CFTR genotypes. The ultimate commercial goal is to develop an experimental system that faithfully predicts the responses to various CFTR therapies on an individual basis.

Public Health Relevance

Invocator is the first drug approved to treat the cause of cystic fibrosis rather than simply manage its symptoms. This drug works in only a small percentage of patients, however; the majority will likely require combinations of drugs to achieve success. A new human cell culture system is being sought to predict how a given patient with a charactistic genetic signature will respond to various drugs, and the proposed project aims to develop such a system utilizing novel methods of cell growth and optical imaging so that each cystic fibrosis patient's cells can be easily analyzed and a treatment protocol developed.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
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Special Emphasis Panel (ZHL1-CSR-I (S1))
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Macgarvey, Nancy
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Progenra, Inc.
United States
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