Many Compounds Cause Cells to
Ignore Dystrophin Gene Errors

Steve Wilton, an MDA grantee at the University of Western Australia in Perth, and colleagues, recently announced that they’ve designed some 300 compounds that can coax cells into skipping over errors in the gene for the muscle protein dystrophin. The majority, he says, have therapeutic potential for treating Duchenne muscular dystrophy (DMD).

Any of hundreds of different mutations (errors) in the dystrophin gene can lead to the absence of this vital muscle protein and thereby cause DMD.

Exon skipping, a technique that causes cells to splice out pieces of genetic instructions (exons) that contain errors, requires tailoring therapeutic compounds to each patient’s specific mutation. “This is the first report showing that every targeted dystrophin exon can be removed,” Wilton said.

In the experiments conducted by Wilton’s group, results of which were published online Feb. 6 in Molecular Therapy, the researchers found that more than 50 percent of dystrophin exons can be efficiently targeted and removed. Wilson said work is continuing to enhance skipping across the entire gene.

Some children with DMD are missing large sections of dystrophin DNA, or carry a defect in a crucial part of the gene, and exon skipping will probably not help them, Wilton says. However, he notes, the majority have small errors in the DNA that either stop dystrophin synthesis too early or cause the cell to interpret the genetic instructions incorrectly. For an estimated 80 percent of these boys, exon skipping would theoretically allow the error-containing genetic region to be spliced out (skipped) and for nearly normal dystrophin protein to be made.

A trial to test the safety of an exon-51-targeting compound designed by the Wilton lab is scheduled to begin in nine boys with DMD this spring in London. “The challenge will be to extend the trials to address other amenable dystrophin mutations as soon as possible,” Wilton said.