DMD Research: Exon Skipping

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.

This announcement, coming just a year after Dutch biotechnology company Prosensa announced positive results for its exon-skipping compound PRO051 bodes well for exon skipping as a treatment for DMD and perhaps for other genetic diseases. (See Trial Results in DMD Heralded as 'Proof of Concept')

Exon Skipping
Exon Skipping: As a cell prepares the final version of instructions for making a protein, it removes excess material and leaves only the exons, the parts that will form the final protein recipe. Laboratory-designed antisense compounds can make a cell eliminate a specific exon along with the other unwanted material.

Like PRO051, AVI4658 is a laboratory-engineered molecule that coaxes muscle cells to ignore, or "skip over," exon (section) 51 of the genetic instructions for the dystrophin protein, the goal being production of nearly normal dystrophin. (Studies of both compounds only accepted participants who could benefit from skipping over this particular part of the dystrophin gene.) Both compounds used a molecular strategy called "antisense" to keep cells from including exon 51.

MDA-supported Stephen Wilton at the University of Western Australia in Perth, and Judith van Deutekom, then at Leiden University in the Netherlads, helped develop AVI4658, 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 solution of 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 (and not those injected with the salt solution) 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. Imperial College London is the trial's sponsor, with AVI BioPharma serving as its clinical development collaborator.

In a press release from AVI BioPharma, Muntoni called the data "exciting" and noted the higher dose of the compound led to an "unequivocal, widespread and robust response" as measured by counting dystrophin-containing muscle fibers.

In the same communication, the company said it will now study the effects of systemic (intravenous) delivery of AVI4658 and that it is developing four related exon-skipping compounds that target different dystrophin exons.

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