Personalized Model Systems to Predict and Investigate CFTR Drug Response in CF

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PROJECT SUMMARY / ABSTRACT Cystic Fibrosis (CF) is the most common fatal genetic disease in Caucasians. CF is caused by mutations in the protein encoding the CF Transmembrane conductance Regulator (CFTR), an ion channel responsible for salt and fluid homeostasis in epithelial tissues. Drugs targeting mutant CFTR, termed “modulators,” hold promise as disease-modifying therapies, but are limited to genotype-specific CF subpopulations. Moreover, extensive and poorly understood subject-to-subject variability in drug response within these populations exists. Both limitations may be overcome through the use of personalized model systems of CFTR function and modulation. The proposed research seeks to validate the use of patient-derived models to predict and understand modulator response. This is a significant milestone towards the ultimate goal of using this approach to drive personalized, precision medicine in CF and to advance biochemical understanding of CFTR modulation. This proposal tests the overall hypothesis that nasal cell models can provide high-fidelity insights into modulator responses in vivo. Pediatric subjects homozygous for F508del CFTR or with a rare CFTR mutation will be recruited from an ongoing study providing robust phenotyping of their clinical response to CFTR modulators. Nasal cells will be cultured and analyzed ex vivo, and compared to the clinical response in each subject. Aim 1 of this proposal tests whether these model systems will predict subjects’ clinical response at the individual level. Aim 2 will then categorize clinical response into responder/non-responder groups and use these nasal cell model systems to investigate primary cellular mechanisms responsible for differential responses. Together, these studies will provide a vertical step towards translation of patient-derived models to inform clinical care and optimize modulator therapies. The PI for this proposal, Dr. Brewington, is an investigator in Pulmonary Medicine with a focus on personalized medicine in CF. He has personally generated the nasal cell model systems and data underlying this proposal. The mentorship team for this proposal includes complimentary expertise in translational CF research (Dr. J.P. Clancy, primary mentor), CFTR biology (Dr. Anjaparavanda Naren, Co-mentor), and research design and execution (Dr. Raouf Amin, Co-mentor). All three have a track record of mentoring success and are dedicated to the proposed work and the PI’s research development. The career development portion of this proposal is foundational to the PI’s transition to research independence, capitalizing on the extensive resources available at Cincinnati Children’s Hospital Medical Center. A combination of formal didactics, direct mentorship, and hands-on experiences will expand Dr. Brewington’s skills in the execution of patient-centered translational research, including analysis of clinical data, model system validation, and advanced biochemical techniques. This training and mentorship will be critical to Dr. Brewington realizing his goal of leading a robust, impactful, and independent research career.