B.S. SUNY Binghamton University, 2011
7th Year MSTP
4th Year Medical Student
Adrian Krainer, PhD, Cold Spring Harbor Laboratory
Antisense-mediated inhibition of nonsense-mediated mRNA of CFTR gene
Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which can lead to respiratory failure. Although CF caused by certain mutations is treatable, there is no treatment for CF caused by the CFTR-W1282X mutation. The W1282X mutation leads to the production of a shorter CFTR protein that is partially functional in low abundance. Ironically, a cellular quality control mechanism called nonsense-mediated mRNA decay (NMD) is responsible for the low level of mutant CFTR protein. In the cells of patients with the CFTR-W1282X mutation, NMD reduces the levels of weakly functional CFTR protein, further compromising the lung function. Drugs called read-through compounds (RTC) that can induce production of the full-length CFTR had limited success to treat CFTR-W1282X. To develop effective therapies for CF, gene-specific NMD inhibition is needed. Exon-junction complexes (EJCs) are protein complexes that mark premature termination codon (PTC)-containing mRNA for NMD. Studies suggest that multiple EJCs bind CFTR-W1282X mRNA to enhance its NMD. Our lab previously developed synthetic antisense oligonucleotides (ASOs) that attenuate NMD in a gene-specific manner, by preventing EJC binding. These ASOs, when combined with RTC, can restore full-length protein levels from nonsense alleles. I plan to develop a set of ASOs to inhibit NMD of CFTR-W1282X mRNA, and use it alone or in combination with RTC to restore the level and function of CFTR protein. The results from this project will provide the basis to establish antisense therapy as a strategy to restore mutant CFTR function.