PTAC/CFTR
Neeraj Sharma, DVM, PHD
Department of Genetic Medicine
Department of Genetic Medicine, Johns Hopkins University School of Medicine
John Lueck, PhD
Pharmacology and Physiology
University of Rochester School of Medicine and Dentistry
Cystic fibrosis (CF) is a common genetic disorder caused by mutations in the CFTR gene which encodes a crucial ion channel regulating fluid balance and pH of the apical extracellular space of epithelial tissues. Loss of CFTR channel function leads to thick mucus, primarily affecting the lungs and causing progressive damage. Over 2,000 CFTR variants exist and are classified based on their effect on the protein. Class I mutations (e.g., nonsense, frameshift, severe splice-site) prevent the synthesis of adequate amounts of functional CFTR channels. While CFTR modulator drugs significantly benefit patients with mutations that retain protein expression (i.e. F508del and G551D), they are ineffective for Class I mutations because there is no protein target, therefore leaving ~ 10% of CF patients without effective therapies and requiring the need for alternative strategies. This session explores novel strategies targeting the DNA and RNA defects in these patients. Four key approaches will be discussed: (1) Understanding the basics of the protein translation and nonsense mediated decay (NMD) to inform treatments, (2) modulating aberrant pre-mRNA splicing to restore proper mRNA transcripts, (3) readthrough of nonsense mutations using combinatorial nucleic acid technologies, and (4) gene editing approaches (e.g., CRISPR-Cas9) in airway cells. The session will cover mechanisms, progress, and challenges for these innovative therapeutic approaches for CF.
Speaker: Bobby Hogg, PhD – National Heart, Lung, and Blood Institute
Speaker: Batsheva Kerem, PhD – Hebrew University
Speaker: Andrei Korostelev, PhD – University of Massachusetts Chan Medical School
Speaker: Sriram Vaidyanathan, PhD – Nationwide Children's Hospital