Human Biglycan Restores Muscle Function in Muscular Dystrophy Mouse Model

Treatment of a mouse model of Duchenne muscular dystrophy (DMD) with the human protein biglycan stimulated repair of the damage caused by the disease to the animals' muscles.

DMD is caused by mutations in the gene that encodes the protein dystrophin and the subsequent disruption of the dystrophin-associated protein complex (DAPC). The disease effects about one of every 3,500 boys whose muscle function is so degraded that they die usually before they reach the age of 30.

Investigators at Brown University (Providence, RI, USA) explored the possibility of manipulating utrophin, a dystrophin homolog expressed at high levels in developing muscle, as a target for DMD therapy. In normal muscle cells, utrophin is located at the neuromuscular synapse and myotendinous junctions. It is necessary for normal membrane maintenance, and for the clustering of the acetylcholine receptor. In adult humans, utrophin RNA is found ubiquitously, being abundant in the brain, kidney, liver, lung, muscle, spleen, and stomach. In the human fetus during muscle differentiation, utrophin is found at the sarcolemma. It disappears when the fetus begins to express dystrophin.

In a paper published in the December 27, 2010, online edition of the journal Proceedings of the [US] National Academy of Sciences (PNAS), the investigators revealed that the extracellular matrix protein biglycan regulated utrophin expression in immature muscle, and that recombinant human biglycan (rhBGN) increased utrophin expression in cultured myotubes (developing skeletal muscle fiber with a tubular appearance). Systemically delivered rhBGN increased utrophin at the sarcolemma and reduced muscle injury in the mdx mouse model of DMD. RhBGN treatment also improved muscle function. RhBGN was well tolerated in animals dosed for as long as three months.

Biglycan consists of a protein core containing leucine-rich repeat regions and two glycosaminoglycan (GAG) chains consisting of either chondroitin sulfate (CS) or dermatan sulfate (DS), with DS being more abundant in most connective tissues. The composition of the GAG chains varies according to tissue of origin. The structure of biglycan core protein is highly conserved across species; over 90% homology has been reported for rat, mouse, bovine, and human biglycan core proteins.

"This is all aimed at getting a therapy that will meaningfully improve the condition of patients," said senior author Dr. Justin Fallon, professor of neuroscience at Brown University. "This is an important step along that path. The next big step is testing in humans.”

In the meantime, the startup company Tivorsan Pharmaceuticals (Providence, RI, USA) licensed rights from Brown University to biglycan, hoping to bring the potential therapy for DMD through clinical trials.

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Brown University
Tivrosan Pharmaceuticals