Duchenne muscular dystrophy (DMD) is an inherited disorder caused by mutation in the gene for dystrophin. Lack of dystrophin causes muscle damage and progressive weakness, beginning in early childhood.
The dystrophin protein transfers the force of muscle contraction from the inside of the muscle cell outward to the cell membrane. Because it connects the center of the muscle cell to the periphery, the dystrophin protein is extremely long. One end is specialized for linking to the muscle interior and the other end is specialized for linking to a variety of proteins at the cell membrane. The long middle section, called the rod domain, is taken up by a series of repeating units called spectrin repeats.
The repeated spectrin units in the middle of the protein play an important role in linking the two ends but studies have shown that the exact number of these units is not critical for the function of the protein as a whole. Many cases of DMD are caused by mutations in the part of the gene that encodes this middle section. Production of the entire protein stops when the mutation is encountered. One treatment strategy is to skip over the mutation, to make a shorter but still functioning protein. That is the strategy behind “exon-skipping” therapies.
The absence of dystrophin sets in motion a cascade of deleterious effects. Fibrous tissue begins to form in the muscle and the body’s immune system increases inflammation. In addition to its force-transfer role, dystrophin provides the scaffold for holding numerous molecules in place near the cell membrane. Loss of dystrophin displaces these molecules, with consequent disruptions in their functions. These include the signaling molecule nitric oxide synthase.
Gene-centered therapeutic strategies for DMD are directed toward replacing the mutant gene, correcting the gene mutation, “skipping” the mutant exon to make a shorter protein, or “reading through” the mutation instead of stopping. Other therapeutic strategies include introducing a similar protein, reducing inflammation, implanting new cells, reducing fibrosis, promoting muscle growth, and mitigating the cellular effects of loss of dystrophin.