News about research in Duchenne, Becker and myotonic muscular dystrophies, and spinal muscular atrophy
Editor's note 2/7/11: A link to the Tivorsan Pharmaceuticals website has been added.
Scientists have found that systemically injecting the human form of a protein called biglycan into mice with a disease resembling human Duchenne muscular dystrophy (DMD) improved the resistance of their muscles to contraction-related damage, restored several proteins to their normal location at the muscle-fiber membrane, and recruited a protein called utrophin to the membrane.
Utrophin closely resembles dystrophin, the protein that's deficient in DMD and Becker muscular dystrophy (BMD). It's likely to compensate to some extent for a lack of dystrophin if it's positioned where dystrophin normally would be.
A pharmaceutical based on biglycan is in development through Tivorsan Pharmaceuticals. Read the full paper for free at Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice. See also Human protein improves muscle function of muscular dystrophy mice and Brown licenses potential muscular dystrophy treatment to Tivorsan Pharmaceuticals.
AVI BioPharma announced Dec. 27, 2010, that incoming CEO and president Chris Garabedian will explore ways to accelerate development of its experimental compound AVI4658 for DMD (see AVI BioPharma Provides Update on Duchenne Muscular Dystrophy Program). AVI4658 is designed to exclude a region called exon 51 from the genetic instructions for the dystrophin protein, allowing muscle fibers to synthesize functional dystrophin protein despite the presence of certain types of DMD-causing dystrophin gene mutations.
In June 2010, the company announced encouraging results from a small trial of this AVI exon-skipping drug conducted in the United Kingdom (see DMD Trial: AVI4658 Increased Dystrophin Production and AVI-4658 Demonstrates First Ever Reported Generation of Greater Than 50% Dystrophin-Positive Muscle Fibers). The company has been planning to start a trial of AVI4658 in the United States, but that has not yet occurred.
Scientists have made the surprising discovery that immature muscle cells taken from people with type 1 myotonic dystrophy (MMD, or DM) can produce proteins that may be toxic and may add to the multiple problems seen in this complex disease. However, these proteins may also become new targets at which to aim therapies.
Until now, most experts have believed that virtually all the problems in type 1 MMD could be explained by the presence of expanded, extra-long strands of genetic instructions (RNA) stuck in cell nuclei, where they disrupt cellular functions. That phenomenon remains crucial to the disease. Now, however, it appears it may not be the whole story.
Some of the RNA apparently leaves cell nuclei, a necessary step for protein synthesis, and some of it apparently is used for protein synthesis even though it lacks the usual "start" signal that tells cells to begin this process.
The study was funded in part by MDA and can be read in its entirety without charge at Non-ATG-initiated translation directed by microsatellite expansions.
Spinal muscular atrophy
A clinical trial of the drug hydroxyurea conducted in people with type 2 or 3 spinal muscular atrophy (SMA) in Taiwan found that, at the dosage tested, the drug did not improve strength, motor function or lung function, or increase production of full-length SMN, the protein that's deficient in SMA (see Randomized, double-blind, placebo-controlled trial of hydroxyurea in spinal muscular atrophy). It had been hoped that the drug would improve function and strength by increasing full-length SMN protein production (see Trial of Hydroxyurea in Spinal Muscular Atrophy).
At the same time, Ching Wang at Stanford (Calif.) University has been conducting two trials of hydroxyurea, one in type 1 SMA and the other in types 2 and 3 SMA (see Pilot Therapeutic Trial Using Hydroxyurea in Type I Spinal Muscular Atrophy Patients and Pilot Therapeutic Trial Using Hydroxyurea in Type II and Type III Spinal Muscular Atrophy Patients). MDA supported the type 1 SMA study.
Although there are as yet no formally announced findings, Wang said the study in types 2 and 3 SMA showed similar results to the Taiwan study, except that his group did find some increase in full-length SMN genetic instructions (RNA) in the hydroxyurea-treated patients. Wang added, however, that his type 1 study findings are "very different." Papers describing both Stanford studies are now in preparation.