Current Research On Duchenne

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 part 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 DGC, which would in turn curb muscle fiber death. Studies with

mice have shown that 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 FK506

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 adenovirus (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 neuromuscular junction, 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 dystrophin. Investigators hope to find the “switch” that creates this change

and reverse its effects.