DMD Research: Drug Company On Board

On Oct. 13, 2009, the multinational pharmaceutical company GlaxoSmithKline announced it will develop and commercialize the experimental “exon skipping” compound PRO051 for Duchenne muscular dystrophy (DMD).

The commitment of a major pharmaceutical company to development of a drug for DMD is very good news for families with this disease.

PRO051 was originally created by Prosensa, a biotechnology company in Leiden in the Netherlands. MDA funded basic science research that Prosensa later used for drug development. Prosensa and GSK will now collaborate to further develop the compound, which has shown promise in a pilot study. (See Trial Results in DMD Heralded as Proof of Concept.)

About exon skipping and PRO051

The regions of genes that carry instructions for proteins (such as dystrophin, the protein that’s missing or deficient in DMD) are known as "exons." During the processing of genetic information in cells, these exons are pieced together, while other information (in the form of "introns") is removed. Then, the final instructions — "messenger RNA"— are exported out of the cell nucleus, at which time the cell can use them to make protein molecules.

PRO051 is an "antisense" compound that causes "exon skipping." Exon skipping using antisense is a technique in which cells are coaxed to reinterpret genetic instructions in such a way that error-containing sections are blocked (not "made sense of" and therefore "skipped"), and a functional protein is synthesized from the remaining instructions.

PRO051 is designed to skip a portion of the dystrophin gene known as exon 51. Skipping exon 51, it's been estimated, could be therapeutic for approximately 13 percent of boys and young men with DMD. (Like other X-chromosome-linked diseases, DMD affects males almost exclusively, although females sometimes develop symptoms.)

Exon skipping diagram  

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.

From 2003 to 2006, MDA supported molecular biologist Judith van Deutekom at Leiden (Netherlands) University Medical Center to develop exon skipping related to the dystrophin gene. She later moved to Prosensa, where she is now discovery director, and continued this work.

In December 2007, investigators who tested PRO051 in four boys with DMD announced the intramuscular injection of the compound was not associated with any apparent adverse effects and that each trial participant showed skipping of exon 51 in the dystrophin gene. Each boy showed properly located dystrophin protein in 64 percent to 97 percent of the muscle fibers in the injected area.

GlaxoSmithKline, headquartered in the United Kingdom with operations in the United States and elsewhere, will obtain an exclusive worldwide license for further development of PRO051 for an initial payment of $25 million and the possibility of future payments to Prosensa.

GSK's Neurosciences Medicines Development Centre will fund all future costs associated with PRO051's development.

Meaning for people with DMD

The commitment of a major pharmaceutical company is a big boost to the development of a drug for DMD. For experimental drugs, the path from a university laboratory to the clinic is complex and expensive and, until now, few large companies have been willing to invest in compounds for rare diseases. GSK's interest in PRO051 substantially improves this compound's chances of reaching patients.

If PRO051 pans out, other exon skipping drugs can be developed for other mutations. Exon skipping may hold promise for treatment of other genetic neuromuscular diseases besides DMD.

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