Although for over a century doctors have recognized a category of inherited diseases that make muscles weak, they didn't know what caused these diseases and there were no treatments for them. It wasn't until the last quarter of this century that advances in our understanding of genetics and molecular biology have allowed us to identify the primary causes of neuromuscular disorders.

Now we know that many disorders that cause muscle weakness arise from within the sequence of chemicals strung together in complex patterns in the center of each of our cells. These chemical strands, known as deoxyribonucleic acid, or DNA, contain the blueprints for all of the proteins that make up our bodies. The portion of DNA that codes for an individual protein is called a gene, and each protein has its own gene.

When the specific sequence of chemicals in a gene is altered, the protein encoded by the gene may be altered as well. If the alterations in the gene (known as mutations) are very disruptive, the protein made from that gene may not get produced at all. Sometimes the protein is still made, but the changes caused by the gene mutation render it nonfunctional. Such mutations are often inherited or they may occur spontaneously before birth.

With MDA funding, researchers have identified many of the genes that, when mutated, cause forms of limb-girdle muscular dystrophy (LGMD). Four of these genes code for a group of closely related proteins (their chemical sequences are similar) called alpha-, beta-, gamma- and delta-sarcoglycan that researchers think normally play an important role in stabilizing the membranes of muscle cells during muscle contraction. These four proteins stick to one another in a group that also includes dystrophin, the protein that's defective or missing in Duchenne muscular dystrophy. This group of membrane proteins is called the dystrophin-glycoprotein complex, or DGC.

Researchers have learned that if one of the sarcoglycan proteins is absent or defective in such a way that it can't bind to the other sarcoglycans, those sarcoglycans tend to be lost from the DGC as well. Depending on the severity of the defect, other members of the DGC, in addition to the sarcoglycans, may be lost, too. The effect can be likened to removing pieces from a house of cards -- some pieces are more important for structural integrity than others. It's thought that the loss of some or all of the DGC allows cell membrane damage to accumulate when the muscle contracts, gradually killing the cells and causing overall muscle wasting and weakness.

With gene therapy, MDA researchers hope to save the DGC by delivering to the muscle cells a healthy, nonmutated copy of the particular sarcoglycan gene that's defective in a person with LGMD. Ideally, the cells will be able to use the healthy sarcoglycan gene to create a functional sarcoglycan protein and restore strength to the muscle membrane.

While this idea sounds good in theory, actually getting a new gene into billions and trillions of individual muscle cells is a daunting task -- especially if you consider that muscle makes up almost half of our body mass. Unfortunately, individual genes made of DNA can't be swallowed like drugs. They'll either be destroyed in the harsh environment of the stomach, or they'll be too large to pass efficiently from the stomach to the bloodstream, and then out of the bloodstream to the muscles.

To get around this problem, researchers have resorted to putting therapeutic genes into modified viruses. Viruses are basically parasites that make their living invading the cells of other organisms, reproducing, then invading more cells. Because viruses are pretty efficient at getting into cells, they make good delivery vehicles, or vectors, to carry therapeutic genes into cells.

At the same time, viruses can be problematic because they may attract unwanted attention from our immune systems. The virus chosen to carry the sarcoglycan genes in the LGMD trial, the adeno-associated virus (AAV), can invade human cells, but doesn't normally cause sickness in humans and doesn't trigger much of an immune response.

For the phase 1 safety trial of LGMD gene therapy, a small foot muscle of each participant will be injected with the AAV vector carrying the appropriate sarcoglycan gene.

If all goes well, some of the individual cells in that muscle will be invaded by the virus and will use the new sarcoglycan gene to begin producing functional sarcoglycan protein. The amount of the vector injected will vary among participants.

Seven weeks after the injection, researchers will take a sample of the muscle and use antibodies to determine whether the DGC proteins have been restored to the muscle membrane. The researchers will also try to determine if the muscle that received gene therapy is healthier than the same muscle in the other foot that didn't receive gene therapy.

The results of the phase 1 trial will determine whether this method of gene therapy with this AAV vector is safe and feasible in humans and, if so, at what dose. Future trials would test muscle strength as well.

Ever since the connection between inherited disorders and genetic mutations was first made, the idea of gene therapy has tantalized researchers as a way to attack the problem at the source, and potentially provide treatments or cures for diseases that aren't otherwise treatable. Unfortunately, gene therapy has proved more difficult in practice than in concept. Early clinical trials for gene therapy in cancer and metabolic disorders proved disappointing.

Now, however, researchers have successfully tackled many of the problems that plagued earlier trials, and many believe that this technique will one day revolutionize the practice of medicine.