Scientists in France and the Netherlands recently announced they've identified a promising new strategy that could potentially become a therapy for oculopharyngeal muscular dystrophy (OPMD), a form of MD that primarily weakens the eyelid and throat muscles and also can affect muscles in the limbs.
The strategy involves using an antibody (immune-system protein) derived from llamas. The antibody sticks to abnormally formed protein molecules in muscle cells and keeps them from forming large, damaging clumps.
The experiments were conducted in fruit flies with the same genetic defect that causes human OPMD. In flies, the defect causes an inability to hold their wings in a normal position.
Martine Simonelig at the Institut de Genetique Humaine in Paris coordinated a group that included MDA research grantee Silvere van der Maarel at Leiden (Netherlands) University Medical Center. The group announced its findings online March 3 in Human Molecular Genetics.
Llamas and related animals, such as camels and alpacas, produce single-chain antibodies, which are not found in humans, whose immune systems make antibodies that consist of two chains.
Unlike double-chain antibodies, these single-chain antibodies can easily be selected and modified to enter and function inside a cell nucleus, which is where the abnormal protein molecules are located in OPMD-affected cells. Antibodies that are expressed inside a cell are known as "intrabodies.”
After testing several llama intrabodies by introducing the DNA for them into the muscle cells of the fruit flies, the researchers chose one, dubbed 3F5, as the most effective in allowing the flies to assume their normal wing posture. They found the 3F5 intrabody didn't reduce the number of protein-containing clumps in the nucleus, but it markedly reduced the size of each clump, presumably reducing its toxicity to the cell.
"We show that llama intrabodies are extremely efficient in vivo [in a living animal]," the researchers say. "This provides strong support for pursuing llama intrabody technology and delivery in therapies."
In this disease, the gene for a muscle protein known as PABPN1 contains an extra section of repeated sequences of the DNA nucleic acids GCG (guanine-cytosine-guanine), which result in synthesis of PABPN1 protein molecules that are too long.
Normally, the PABPN1 gene contains six GCG repeats, which lead to the inclusion of six molecules of alanine in each PABPN1 protein molecule. But people with OPMD have eight to 13 GCG repeats, resulting in a protein that contains between eight and 13 extra alanine molecules.
These extra-long PABPN1 molecules form large clumps (aggregates) in the nuclei of cells. Scientists believe these are the likely cause of muscle-fiber degeneration and weakness in OPMD.