Jan. 23, 2009

Second DMD Exon-Skipping Trial Promising

On Jan. 21, AVI BioPharma of Portland, Ore., announced its experimental compound AVI4658 for the treatment of Duchenne muscular dystrophy (DMD) yielded promising results in a phase 1 clinical trial in the United Kingdom.
 
AVI4658 is a laboratory-engineered molecule that coaxes muscle cells to ignore, or "skip over," a section (exon) of genetic instructions for the dystrophin protein, which is missing in DMD patients. The strategy, known as "exon skipping," is designed to cause cells to make nearly normal dystrophin molecules.

The AVI4658 construct, which specifically targets exon 51 of the dystrophin gene, was developed by an international team of investigators that included MDA-supported Stephen Wilton at the University of Western Australia in Perth and Judith van Deutekom, then at Leiden University in the Netherlands, working in collaboration with AVI BioPharma.

The study, which involved fewer than 10 DMD-affected boys between 12 and 17 years old, was conducted at Hammersmith Hospital in London and at the Institute of Human Genetics of the University of Newcastle Upon Tyne (U.K.).

Each boy received an injection of either 0.09 or 0.9 milligrams of AVI4658 into a foot muscle and a salt solution into the corresponding muscle on the other foot. Three to four weeks later, each injected muscle was examined for evidence of dystrophin production.

Results showed the AVI4658-injected foot muscles produced dystrophin in all participants, and that the amount produced correlated with the injected dose. All participants tolerated the compound well, and there were no significant adverse events related to its administration.

The trial was funded by the U.K. Department of Health and led by Francesco Muntoni at Imperial College London, who has MDA support to study another muscle disease.

"As a clinician and scientist, I am very pleased by these findings and the prospects they offer for the potential treatment of this serious, life-threatening condition," Muntoni said in a Jan. 21 company press release. "Biopsies from muscles injected with the higher dose of test drug showed an unequivocal, widespread and robust response in terms of number of dystrophin positive muscle fibers. We will publish these exciting data in a peer-reviewed journal in due course."

The company says it will now study the effects of systemic (intravenous) delivery of AVI4658. It's also developing four related exon-skipping compounds that target different dystrophin exons.

In December 2007, the Dutch biotechnology company Prosensa announced positive results for its exon-skipping compound, PRO051. In that study, conducted in the Netherlands and reported in the Dec. 27, 2007, issue of the New England Journal of Medicine, four boys with DMD between ages 10 and 13 began producing dystrophin after receiving injections into a leg muscle.

MDA is funding studies to develop exon skipping and related strategies to treat DMD and other diseases.