Duchenne’s muscular dystrophy is the result of a defective gene on the X chromosome. This gene is responsible for production of the muscle protein dystrophin. Dystrophin is an integral pan of the dystrophin-glycoprotein complex which bears the brunt of the force generated during muscular contraction. When dystrophin is not produced, the dystrophin»glycoprotein complex (DCG) is not present. Absence of the DCG leads to tears in the muscle membrane because the muscle membrane bears the force of muscular contraction alone.
Tears in the muscle membrane allow substances to leak in and out of the muscle fibers at random. This uncontrolled “biochemical traffic” leads to eventual death of the muscle fibers. Most of the current research on Duchenne’s muscular dystrophy involves gene therapy. Researchers are attempting to find ways to introduce a healthy dystrophin gene into the afflicted individual.
This healthy gene would produce the dystrophin protein thereby regenerating the DOC, which would in turn curb muscle fiber death. Studies with mice have shown that the introduction of the dystrophin gene is effective in treating Duchenne’s muscular dystrophy.
However, introduction of the dystrophin gene into the body is no easy task. Thus, many scientists are focusing their research on ways to present the gene to the body. Viruses have a natural inclination to deposit their genetic material in a cell’s nucleus and thus are primary candidates for gene transport. The dystrophin gene is a relatively large gene and therefore must be delivered via an adenovirus. The problem with viral delivery is that the immune system of the recipient recognizes the virus as foreign and destroys both the virus and the protein it is carrying.
Researchers at the University of Michigan-Ann Arbor have developed an adenvirus that is “gutted” of its own genetic material and consists only of a viral shell. These “gutted” adenoviruses elicit fewer immune responses. However, it is believed that immunosuppressant drugs. such as FKSOS may be necessary to fully overcome the immune response to adenovirus-based gene therapy. All current gene based research has been performed on animals, but this fall, investigators at the University of Ohio-Columbus and the University of Michigan—Ann Arbor will begin a very limited human trial of gene therapy in Duchenne’s muscular dystrophy. The major goal of the 24 week study is to establish the safety of the gene transfer procedure The study involves 12 participants with Duchenne’s muscular dystrophy and is waiting for final approval from the Food and Drug Administration. Another focus of research on Duchenne’s muscular dystrophy involves the protein Utrophin. Utrophin is almost exactly like dystrophin, and its potential as a replacement for dystrophin has stirred much interest. Utrophin genes could be introduced into the body via an adenovims (described above) and “fill in” for the missing dystrophin protein.
The major advantage of utrophin over dystrophin is that individuals with the disorder already make utrophin, so their immune systems would accept the protein and not reject it as foreign. Utrophin is coded for on chromosome 6 and is thus unaffected by the defective X chromosome. Therefore, another method of increasing utrophin would be to manipulate the utrophin genes already present in the muscle fibers to produce more Utrophin is normally found only at the neuromuscularjunction, but to be effective, it must completely surround the muscle fiber. Researchers have found that during fetal life, humans exhibit utrophin around the entire muscle fiber, but as development progresses, the utrophin is replaced with dystrophini Investigators hope to find the “switch” that creates this change and reverse its effects.