Gene Upregulation
Upregulation of utrophin
Utrophin is a protein with a structure and function very similar to dystrophin. In humans, its gene is located on chromosome 6, it has 75 exons and is about one million base pairs long. The utrophin protein is about 7% shorter than dystrophin. It is present in many body tissues, also in muscle, but there it is concentrated in regions where the motor nerves contact the muscle membrane, the neuromuscular junctions. Utrophin exists in two slightly different forms A and B. The muscles contain only the A-form. Before birth, the utrophin concentration in muscle is much higher than afterwards. Mdx mice whose utrophin gene was knocked out experimentally, which thus have neither dystrophin nor utrophin, have Duchenne-like symptoms and die early in contrast to “normal” mdx mice whose muscles show less severe damage. Experiments with mice have shown, that utrophin, if it is present in larger amounts, can replace dystrophin.
These mice were transgenic mice who contained utrophin mini genes in their germ line, introduced by a technique that cannot be used in humans. By increasing the amount of utrophin by a factor of three to four, the development of 9 the dystrophic symptoms could be prevented and led to a complete functional recovery.
It has recently been found that Duchenne boys who have slightly higher amounts of utrophin in their muscles lose their walking ability later than those with the normal low amount. This is an indication that increasing utrophin would work like in mice and prevent or retard the degradation of the muscles. For a possible Duchenne therapy, one should try to increase the low amount of utrophin by upregulation of the activity of its gene. To achieve this, an activating substance is needed, which could well be a known drug, or some other chemical or a naturally occurring substance, that would react with the promoter of the gene. The small molecules of such a compound could probably enter the muscle cells easily, and if they are known drugs, they would not need lengthy approval procedures.
Günter Scheuerbrandt,(2006)