Pharmacological approaches for targeting cystic fibrosis nonsense mutations.

European Journal of Medicinal Chemistry
Jyoti SharmaSteven M Rowe

Abstract

Cystic fibrosis (CF) is a monogenic autosomal recessive disorder. The clinical manifestations of the disease are caused by ∼2,000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It is unlikely that any one approach will be efficient in correcting all defects. The recent approvals of ivacaftor, lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor represent the genesis of a new era of precision combination medicine for the CF patient population. In this review, we discuss targeted translational readthrough approaches as mono and combination therapies for CFTR nonsense mutations. We examine the current status of efficacy of translational readthrough/nonsense suppression therapies and their limitations, including non-native amino acid incorporation at PTCs and nonsense-mediated mRNA decay (NMD), along with approaches to tackle these limitations. We further elaborate on combining various therapies such as readthrough agents, NMD inhibitors, and corrector/potentiators to improve the efficacy and safety of suppression therapy. These mutation specific strategies that are directed towards the basic CF defects should positively impact CF patients bearing nonsense mutations.

Citations

Oct 23, 2020·Biological Reviews of the Cambridge Philosophical Society·Martine Palma, Fabrice Lejeune
Jan 5, 2021·Frontiers in Physiology·Jyoti SharmaSteven M Rowe
Dec 17, 2020·International Journal of Molecular Sciences·Silvia LombardiAlessio Branchini
Mar 11, 2021·European Journal of Medicinal Chemistry·Tiziano Bandiera, Luis J V Galietta
May 1, 2021·Antibiotics·Rosa María Girón MorenoRosa Mar Gómez-Punter
Oct 19, 2021·The Plant Journal : for Cell and Molecular Biology·Soheila BayatTerezie Mandáková

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