Editor's note 2/15/12: On Feb. 15, 2015, Justin Fallon and colleagues announced in the Journal of Neuroscience that they have identified an additional role for biglycan; namely, that it stabilizes connections between nerve and muscle fibers. The work, funded in part by MDA, is summarized in a press release from Brown University. It could have implications for amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), the investigators say.
TVN-102 is an experimental drug based on biglycan, a naturally occurring protein found in the membrane surrounding each muscle fiber. Biglycan is part of a cluster of proteins located at intervals in the membrane. These shock-absorbing clusters appear to protect the membrane as muscle fibers contract and relax.
Normally, the muscle protein dystrophin also is part of the membrane protein clusters. But in DMD, dystrophin is lacking, causing membrane fragility and structural and functional abnormalities of skeletal muscles. In BMD, a partially functional dystrophin protein is made, presumably affording some protection for fiber membranes. People with BMD have a higher level of skeletal-muscle function than those with DMD.
Laboratory experiments have shown that the utrophin protein, which is similar in structure to dystrophin, can occupy the position that dystrophin normally occupies at the muscle-fiber membrane in skeletal muscles and that it can provide some compensation for dystrophin deficiency in animals. People with DMD and BMD make utrophin, but not enough to compensate effectively for dystrophin deficiency.
Developing biglycan as a potential treatment for DMD or BMD has been a major focus of the laboratory of neuroscientist Justin Fallon at Brown University in Providence. MDA supported Fallon's research at Brown between 1994 and 2000.
In a paper published online in Proceedings of the American Academy of Sciences USA in December 2010, Fallon and others showed that biglycan acts like a molecular "magnet," attracting utrophin to the muscle-fiber membrane. (See Biglycan Recruits Utrophin to the Sarcolemma and Counters Dystrophic Pathology in mdx Mice.)
They also showed that giving systemic injections of biglycan to dystrophin-deficient mice with a DMD-like disease caused utrophin to accumulate at the right position near the membrane, and that the treatment reduced structural muscle abnormalities and improved muscle function.
In September 2010, Brown University licensed the biglycan technology developed by Fallon's lab to Tivorsan for further development of biglycan as a DMD/BMD treatment.
The new MDA funding will allow Tivorsan to conduct further laboratory testing of TVN-102 and to do the ground work necessary to obtain permission for human testing of the drug from the U.S. Food and Drug Administration (FDA).
Tivorsan hopes to have completed animal testing and other FDA-required studies of TVN-102 and to request permission for human trials of the drug by late 2012. The company hopes to begin human testing of TVN-102, probably in healthy volunteers without DMD or BMD, in 2012 or 2013.
If the preliminary studies show the drug is safe and well-tolerated and that it has the potential to be effective in treating DMD or BMD, tests in people with one of these diseases will likely follow.
Increasing membrane-associated utrophin may have an advantage over replacing dystrophin in treating DMD and BMD because the immune systems of people with DMD and BMD are more likely to accept these proteins than they are dystrophin. There's evidence that, at least in some with DMD, the immune system does not tolerate functional dystrophin protein.
Biglycan and utrophin are normally produced in people with DMD and BMD and theoretically should be tolerated by the immune system.
Any of a number of mutations in the dystrophin gene can result in DMD or BMD and many current strategies (i.e., exon skipping) are being developed only for specific dystrophin mutations.
By contrast, increasing membrane-associated utrophin has the potential to help everyone with DMD or BMD, regardless of the specific mutation in the dystrophin gene.
In normal muscle fibers, the dystrophin protein is part of each protein cluster in the muscle-fiber membrane. A ring of such clusters surrounds each fiber. Utrophin can occupy the same position as dystrophin and can help compensate for dystrophin deficiency. Biglycan (not shown) is part of the same membrane-associated protein cluster.