Exon Skipping Drugs



Eteplirsen CAS# 1173755-55-9

In Eukaryotes, RNA destined to become messenger RNA (mRNA) is composed of exons and introns. Normally, during post-transcriptional processing, introns are removed and the exons are “stitched” together to form a functional mRNA that is used for protein synthesis. In some genetic diseases a mutation in the DNA  is expressed in an exon resulting in disruption of the reading frame of an mRNA molecule. In such cases the resulting protein is nonfunctional. Certain drugs are being/have been developed that allow cellular machinery to skip over the offending exon and express the proper reading frame, producing an mRNA that, in turn, produces a truncated (shorter) but functional or partially functional protein.

In individuals with Duchenne Muscular Dystrophy, mutations in exons result in production of nonfunctional dystrophin a protein that normally prevents damage to muscle proteins when they contract. A new drug, Eteplirsen (Brand name Exondys), that promotes exon skipping has recently been approved to treat individuals with this form of muscular dystrophy. Its approval by the FDA, however, is controversial, in part, because of the small sample size used to assess the efficacy of the drug. Also of concern is the extraordinary expense ($300,000/year) of this drug.

The Chemical and Engineering News (see link below) provides a nice overview concerning this drug and its controversial approval by the FDA.

Jarvis, L.M. (2016) Aftereteplirsen: Duchenne stakeholders contemplate what comes next, Chemical and Engineering News, November 14, 2016, pp. 26-41.

Eteplirsen Image source: (http://lgmpharma.com/product/eteplirsen/)