’s Muscular Dystrophy Essay, Research Paper
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.