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49 - Genetics and Pathophysiology of Cystic Fibrosis
Book chapter

49 - Genetics and Pathophysiology of Cystic Fibrosis

Garry R. Cutting, John Engelhardt and Pamela Leslie Zeitlin
Kendig's Disorders of the Respiratory Tract in Children, pp.757-768.e6
Elsevier Inc, Ninth Edition
2019
DOI: 10.1016/B978-0-323-44887-1.00049-3

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Abstract

Our understanding of the role of disease-causing variants in CFTR has culminated in two new variant-specific CFTR modulator therapies approved by the US FDA. These modulators target defects in CFTR biogenesis and in channel gating. Clinical trials are directed to improving the efficacy of these first-generation molecules. However, other CFTR variants that lead to nonsense-mediated decay, aberrant splicing, and reduced gene expression are refractory to CFTR modulators and will require new therapeutic approaches. To this end, new CF animal models are yielding key insights into tissue-specific disease mechanisms, such as impaired mucociliary clearance and pancreatic dysfunction. Although infection and inflammation remain challenging to treat, progress in targeting CFTR directly will result in individuals with CF living longer. To maximize life span, earlier interventions, soon after diagnosis, are needed. Finally, the advances in precision medicine for CF may benefit more common disorders such as COPD and pancreatitis where CFTR dysfunction contributes to pathophysiology.
CFTR chloride DNA variant nonsense-mediated decay protein folding sodium splicing

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