Summit C1100
Summit are a UK based biotech company that have a strong interest in developing drugs for Duchenne. Summit was set up by Kay Davies and others from the work at the University of Oxford labs on researching ways to upregulate the Utrophin gene as a possible subsitiute for dystrophin.
Summit is now working with Action Duchenne through the ZF Partnership to accelerate their Utrophin upregulation programme and to discover new drugs for Duchenne.
Summit have a lead Utrophin uprregulator SUM C1100.
From a report of the PPUK (now Action Duchenne) Conference 2006 by
Utrophin to replace dystrophin:
Kay Davies of Oxford University is one of the “giants” who in the 1980s worked like Louis Kunkel on finding the gene which causes Duchenne muscular dystrophy when inactivated by a mutation. They were then and still are in a friendly competition to find a treatment, they exchanged students and, as is usual among scientists with the same goal, they meet often, discuss their work and their ideas and plans and thus stimulate each other’s work. The research field of muscular dystrophy has produced remarkable results in the last years so there will be several effective treatments for this terrible disease.
There are four great challenges that have to be met by anybody trying to find a therapy for Duchenne dystrophy: (1) Dystrophin is a huge protein whose function has to be restored; (2) to make a difference, at least 20% of the normal level of dystrophin has to reappear again, or if not this protein, then another one like utrophin which can replace it; (3) this must happen in all skeletal muscles, and in those of the heart and lungs, also; and (4), any immune reaction against a new protein has to be avoided. When Dr. Davies and her colleagues tried to find the Duchenne gene, they found instead this other protein, utrophin, and its gene, and they started to use simple compounds as drugs to upregulate the low amount of this protein in muscle tissue. Such drugs may have side effects but because they are small molecules and not proteins, they do not produce immune problems, and will be easy to deliver into the blood circulation to reach all muscles. 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 12 base pairs long. The utrophin protein is about 7% shorter than dystrophin. Like dystrophin, it connects the F actin structure in the cells with a protein complex in the membranes similar to the dystrophin associated complex.
Utrophin is present in many body tissues, also in muscle, but there it is concentrated in regions where the motor nerves contact the muscle membranes, the neuromuscular junctions. If utrophin and dystrophin are so similar, why does nature not use utrophin when dystrophin is missing in Duchenne patients? There are indications, that nature really tries this. In Duchenne patients, utrophin starts to spread from the nerve-muscle junctions to the muscle membranes. The more utrophin a patient has, the later he must use a wheelchair. That is an indication that upregulation of utrophin would make Duchenne dystrophy more benign.
During development at 12 weeks, the muscles have both, utrophin and dystrophin, then utrophin disappears from the cell membranes, remains only at the neuromuscular junctions, and at birth dystrophin alone remains on the membranes. Thus utrophin is a fetal form of dystrophin. This means, that if one could reactivate the developmental program for utrophin, one would get a treatment for Duchenne dystrophy. Mdx mice whose utrophin gene was knocked out experimentally, which thus have neither dystrophin nor utrophin in their muscles, have Duchenne-like symptoms and die early in contrast to “normal” mdx mice whose muscles show less severe damage. In other experiments with transgenic mdx mice which had utrophin mini genes in their germ line, introduced by a technique that cannot be used in humans, it could be shown, that utrophin, if it is present in larger amounts, can replace dystrophin. By increasing the amount of utrophin by a factor of three to four, the development of the dystrophic symptoms could be prevented and this led to a complete functional recovery. Thus, for a possible Duchenne therapy, one should try to increase the low amount of utrophin by upregulation of the activity of its gene.
The gene is now well known, but 20 years ago, it took two years to find and characterize it, today that could have been done in two weeks. The gene has two different start sites, promoter sequences, to which signaling compounds bind to initiate the synthesis of the utrophin protein. One promoter induces the production of one form of utrophin, the A-form, in the regions of the neuromuscular junctions. The other promoter starts to make the other form, the B-utrophin, in the blood capillaries. One part of the promoter sequence, the N-box, contains a stretch of six nucleotides, TTCCGG, that seem to be responsible for confining the A-utrophin to the musclenerve junctions. The researchers are now trying to interfere with this signaling process so that more of the A-form of the utrophin is made and directed to the muscle cell membranes where it would possibly occupy the sites vacated by dystrophin in Duchenne boys. Even before all these molecular details of the utrophin biology was elucidated, work started to find a substance that could upregulate utrophin and properly direct it to the membranes.
That could not be done in a university laboratory. So Kay Davies looked for a pharmaceutical company that would be interested in this difficult and expensive task, and as she could not find one, she herself founded a new one: VASTox plc. (now Summit) in Abington near Oxford.
Jon Tinsley Summit Plc
of this company then reported in a separate presentation how much has been done to find a potential utrophin drug: Until now, 13,000 chemical compounds have been screened for their ability to upregulate the activity of the utrophin gene in mdx mice. The light-producing enzyme luciferase from fireflies was used in a reagent system to test for the presence of utrophin. More than 100 promising substances were found which could increase the low utrophin concentration three- to fourfold. They are now being optimized and tested on muscle cell cultures and in living mdx mice with the aim to increase the efficiency further and to assure that utrophin is sufficiently upregulated in all muscles of the animals.
One of the most active compounds, VOX185, has already been tested systemically in mice by injection into the abdomen. It reacts only with the promoter of the A-form of utrophin, that is present in muscle. The A-utrophin in all of the skeletal muscles of the mice tested could be upregulated two to threefold, but it is not known yet, whether the utrophin in cardiac muscles is upregulated also. After 12 weeks of weekly systemic injections, the animals showed a significant recovery of their muscular function. This and other active compound are now being optimized further by chemical modifications.
Clinical trials with Duchenne patients are being prepared now and could start in 2008.