Scientists in the United Kingdom have found that mice carrying a genetic mutation that causes oculpharyngeal muscular dystrophy (OPMD) in humans and showing a disease resembling human OPMD benefited from treatment with a chemical called cystamine, provided in their drinking water.
About the new findings
David Rubinsztein and colleagues at the University of Cambridge announced their findings June 2, 2010, in Science Translational Medicine.
They found that mice with an OPMD-like disease showed better muscle function and strength compared to untreated OPMD mice; and that their muscle fibers showed fewer abnormal clumps and fewer markers of cell death than those of their untreated counterparts.
The investigators believe cystamine's benefits result from its interference with an enzyme called transglutaminase 2 (TG2), which shows enhanced activity in OPMD mice.
The underlying cause of OPMD is a mutation in the gene for a protein called PABPN1 that causes extra alanine molecules to be inserted into the protein.
The mice in these experiments had a mutant PABPN1 gene inserted that caused them to have extra alanines in each PABPN1 protein molecule, as do humans with OPMD.
In humans and mice, PABPN1 mutations result in the presence of abnormal clumps ("aggregates") inside muscle fibers and in a cell-death process called apoptosis. It isn't clear if the large aggregates themselves are the most toxic disease-related phenomena, although the aggregation process is likely to cause damage.
In humans, the disease usually begins in middle age (30s to 50s) and results in progressive weakness, starting in the muscles of the eyelids or throat and often spreading to the limbs. (For more about OPMD, see In Focus: Oculopharyngeal Muscular Dystrophy.)
In mice, weakness is more generalized and starts at about 4 months of age. As in humans, it's accompanied by the formation of aggregates and excessive apoptosis in muscle fibers.
Meaning for people with OPMD
In their June paper, the researchers say that the beneficial effects of cystamine in an OPMD mouse model suggest that the target of this drug (interference with TG2) may be worthy of further consideration in this disease.
Cystamine isn’t routinely used in humans, but cysteamine, which is converted to cystamine in the body, may be suitable for OPMD treatment, Rubinsztein said. He noted that cysteamine is used to treat cystinosis, a disease involving an abnormal accumulation of the amino acid cysteine.
"Trials of cysteamine could be considered in OPMD, and it may be possible to identify safer molecules that inhibit TG2 that could be suitable for long-term use in OPMD," Rubinsztein said.