making muscle wasting history

Utrophin is a protein with a structure and function very similar to dystrophin. In humans, its gene is located on chromosome 6, has 75 exons, and is about one million base pairs long. Utrophin is present in many body tissues, also in muscle, but there it is concentrated at the neuromuscular junctions, where the motor nerves contact the muscle membranes. At 12 weeks during the fetal development of a child, the muscle membranes contain both, utrophin and dystrophin, and then utrophin disappears until at birth only dystrophin alone remains there. Thus utrophin is a fetal form of dystrophin. Mdx mice whose utrophin gene was knocked out experimentally, which have neither dystrophin nor utrophin in their muscles, have Duchenne-like symptoms in contrast to “normal” mdx mice whose muscles show less severe damage in spite of the absence of dystrophin. By increasing the amount of utrophin in mdx mice three to four-fold with genetic techniques, which cannot be used in humans, the development of the rather light dystrophic symptoms of the mdx mice could be prevented. In Duchenne patients, utrophin starts to spread from the nerve-muscle junctions to the muscle membranes, and the more utrophin a patient has, the later he must use a wheelchair. This means, that the upregulation of the utrophin gene would lead to a treatment for Duchenne dystrophy.
Utrophin exists in two similar forms, but only the Autrophin is exclusively located in rather small amounts at the neuromuscular junctions of all muscle cells.

The researchers started to look for substances that could upregulate the gene for A-utrophin and then direct this protein to the muscle cell membranes where it would occupy the sites vacated by dystrophin in Duchenne boys.

This research and development work was started by Prof. Dame Kay Davies of the University of Oxford, and is now being continued by the company Summit plc near Oxford under the direction of Dr. Jon Tinsley. At the end of 2007, over 30,000 chemical compounds have been screened for their ability to upregulate the activity of the utrophin gene in tissue cultures from mdx mice. A number of active compounds were identified and the most promising ones are now being optimized and tested in living mdx mice with the aim to increase the amount of A-utrophin sufficiently in all muscles of the animals.
Additional screening tests with dystrophic zebrafish are ongoing which will possibly identify other pharmacological drugs for treating Duchenne dystrophy. Zebrafish embryos are very small (2-3 mm), transparent and are fully developed by 24 hours. The muscle structure can be easily seen and analyzed under the microscope when viewed under polarized light. Muscle pathology (diseased muscle structure) of the embryos without dystrophin is very similar to Duchenne muscle. After further optimization, one of the most active compounds, SMT C1100, led to recovered muscle function in mdx mice, because their degeneration, fibrosis, fat deposition, and chronic inflammation were reduced significantly.

After daily injections for 28 days, no side effects appeared If ongoing preclinical toxicology and manufacture continues to be successful, safety trials with healthy volunteers could begin in 2008, followed by clinical trials with Duchenne patients in 2009.

This project has now been taken over by Biomarin Pharmaceutical Inc