Currently, CoQ10 therapy is being tried in Phase III for HD (the 2CARE trial funded by NIH in the USA). There is plenty of evidence supporting a mitochondrial disturbance in HD. The hypothesis behind CoQ10 therapy is that there is an energy deficit in HD which can be ameliorated by CoQ10 supplementation. In several studies in patients and in animal models of HD, scientists have reported changes in energetic measures such as the ratios between ATP and ADP (energy ‘currency’ of the cells), lactate/pyruvate (a measure of the relative energetic contribution of glycolysis vs mitochondrial driven energy contribution) and creatine/phospho-creatine. All of these measures are highly suggestive that HD patients have a basic (some argue causal) disturbance in energy homeostasis. The primary site for these observed deficits appears to be the mitochondrial electron transport chain, a set of biochemical events whereby electrons flow through the mitochondria to generate ATP, the energy ‘currency’ of the cells. It is well known that many mental disorders can arise directly from energetic disturbances. In fact, most genetic disorders affecting genes involved in mitochondrial function lead to severe mental problems. The hypothesis is therefore an attractive one. CoQ10 functions in the electron transport chain to allow for the ‘shuffling’ of electrons in and out of the mitochondria, facilitating energetic processes. In fact, HD patients display muscle wasting and other symptoms which might arise from a deficiency in energy metabolism.
Hence the rationale for using CoQ10 supplementation as a way to treat HD. The evidence suggests that there might be some benefit to CoQ10 therapy for a variety of neurodegenerative disorders, including HD. The main objection to the use of CoQ10 is that, although safe, the distribution of CoQ10 to the brain is not optimal, and saturated at doses well below those being studied now in the context of the 2CARE trial funded by the NIH. That is, more will not be better.
Instead, CHDI approached Edison Pharmaceuticals a few years ago to explore the option of generating ‘better CoQ10s’, which would access the brain mitochondria more efficiently, would be more potent (that is, patients would need to take less amount to have greater benefits). Through medicinal chemistry approaches, Edison developed novel molecules which could function just like CoQ10, but were much more potent (1000 times more) and got into the brain much more readily. Those molecules were shown to act like CoQ10 since in vitro, in cells, they could rescue a genetic lesion in a CoQ10 precursor, and could also prevent the death of mutant Huntingtin expressing cells (patient-derived blood cells). This made Edison and CHDI realize that this could be a viable strategy for treating HD.
Edison’s mission was to develop new avenues to treat energetic disorders. Many of these arise because genes involved in mitochondrial function are mutated in many childhood disorders, such as Leigh syndrome. See http://en.wikipedia.org/wiki/Leigh_syndrome for more information on this disorder. The goal for Edison was to exploit nature to develop better, more potent, molecules, which could mimic what some natural vitamins do in the body. EPI-743 was one of such molecules which works in the mitochondria to increase energy efficiency.
At our Palm Springs meeting, Dr. Guy Miller (CEO)of Edison described some recent, exciting news with EPI-743. The FDA recently granted Edison compasionate use for EPI-743 to treat children with Leigh syndrome that were in a terminal stage. This was due to the fact that these kids would die without any intervention, Hence there was no risk in trying anything new. Remarkably, ten people have now been treated with this molecule, and they seem to be doing very well. Not only did they not get worse, they did better!
This is good news for HD: the molecule appears well tolerated, without any major side effects, and some of the kids who took it have been improving. Some of them were expected to have died by now, and even their brain scans have revealed that they seem to be doing better, contrary to what we would have predicted.
It is still very early days to see if this approach will work in HD. Part of the problem is that we do not fully understand whether the energy deficits in HD can be treated via this mechanism, and if these deficits affect all people carrying the mutation in Huntingtin. But we are trying to get answers to these questions by testing HD patients in exercise tests to better define the type of energy dysfunction they have, and to assess whether these deficits can be brought to normal by EPI-743. At the moment, all I can say is that we remain very committed to further understanding these deficits and to assess whether this type of approach can be applied to HD. We are currently internally discussing how best to design clinical studies to assess how best we can tackle this problem. I remain hopeful, but I don’t want to instill a false sense of hope: as with every clinical study, success depends on how well we can measure the effect, and how significant the dysfunction is to the overall cause for the symptoms categorized as ‘HD’
The point of this entry is to communicate that there are new strategies emerging, based on more solid science, and which we hope to bring into patients soon. Stay with us and remain hopeful!