With all the talk of new gene discoveries in recent years, the Sunday morning scientific session returned to the original discovery in 1993 that mutations in the SOD1 gene were responsible for around a fifth of familial (inherited) MND cases and 2-3% of all cases of the disease.
Although much of our understanding of MND in the past two decades comes from SOD1 laboratory models of the disease, we still don’t know exactly how SOD1 kills motor neurons. But that hasn’t stopped several groups from working on a number of innovative ways of protecting motor neurons from SOD1 toxicity. Although focused on a relatively rare form of MND, some of the strategies being followed could potentially also be applicable to other forms of the disease.
Switching off the SOD1 gene
One school of thought is that if the SOD1 gene is causing toxic effects, then could we somehow try to switch off – or at least tone down – the gene? This is the approach that is currently being tested in a small clinical trial by Isis pharmaceuticals Inc using molecules called antisense oligonuecleotides.
Dr Loreiei Stoica from Massachusetts Medical School, kicked off the session by introducing a slightly different approach, switching off the SOD1 gene using another technique. Using the SOD1 mouse model, the researchers were able to reduce the gene activity in the spinal cord by over a third, leading to a 50% increase in survival. However, some animals did show side effects that need to be explained before this approach can be considered for the clinic.
Controlling bad behaviour
In Victorian times, a young lady of standing would not be seen in the company of young men without a chaperone. The chaperone would act as a minder and steer the young lady away from any ‘inappropriate liaisons’!
In cells, ‘chaperone’ proteins help to keep the SOD1 protein to maintain its correct structure. Without them, the SOD1 protein can unravel and this makes it rather promiscuous, sticking to any other protein that happens to come along.
Dr Ari-Lev Gruzman (Bar-Ilan University) and colleagues have created and tested a variety of chemical ‘SOD1 chaperone’ compounds in cells containing the mutant SOD1 gene. They performed a variety of studies in the cell cultures, taking the most potent compound forward for testing in the SOD1 mouse model and observed a slowing of disease symptoms, but not an overall effect on survival.
Call the Copper
Normal SOD1 needs copper to work properly and a lack of copper can cause the molecule to malfunction. With the mutant SOD1, this effect is even more pronounced. Dr Joe Beckman (Oregon State University) has exacerbated this effect using genetically modified SOD1 mice meaning that there is very little copper available for the SOD1. This in turn causes a very rapid disease course in the animals.
The question therefore arises as to whether increasing central nervous system (CNS) copper levels could slow the disease. This cannot be done through dietary means, as copper does not cross the blood brain barrier – in fact to get any appreciable amount of copper into the brain would require such high levels in the blood that it would be toxic.
What is needed is a drug molecule that can deliver copper to the CNS, but also keeping the blood levels low. Dr Beckman showed that a compound called CuATSM had a pronounced effect in slowing disease progression in his modified ‘low copper’ SOD1 mice. CuATSM is used in cancer research to improve the resolution of PET scans in patients with brain tumours by delivering radioactive copper, so Dr Beckman’s rationale is that is can just as easily deliver ‘normal’ copper. The fact that this compound is already used in cancer patients should help the researchers in moving this into clinical studies in SOD1 MND.
Stop the spread
We know from several elegant studies performed in recent years that the toxic SOD1 can be released by sick neurons to ‘infect’ neighbouring more healthy neurons. It is believed that this propagation process could partially explain the rapid progression of the disease through the brain and spinal cord – with SOD1 protein (or other molecules in other forms of MND) acting a bit like sparks in a forest fire, causing it to spread. Using cell cultures, Dr Leslie Grad (University of British Columbia) has developed a means of monitoring this spread of SOD1 protein from one cell to another, which allows him to test compounds that may soak up any SOD1 protein that is released.
Dr Grad has identified a part of the protein structure that appears to be crucial for the propagation to occur. Using computers, he has started to design more ‘drug-like’ compounds for testing, based on a molecule called uridine, which he has found is able to reduce SOD1 propagation in lab studies. This is early stage work, but has the advantage that it does not necessarily rely on the dugs getting inside cells, although they still need to be designed to get from the blood into the central nervous system.