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Energy metabolism is known to be impaired in Huntington's Disease. Both creatine and CoQ10 boost energy in the cell. In addition both act as antioxidants. Phase III clinical trials have been funded for both. The creatine trial will begin recruiting later in 2008; the CoQ10 trial has already started.
Ethyl EPA is a purified version of eicosapentaenoic acid, an Omega 3 fatty acid found in fish oil. A Phase III clinical trial managed by the Huntington Study Group and sponsored by Amarin Pharmaceuticals was suggestive of benefit after six months of use but not conclusive. There may be an additional trial to resolve the issue.
Dopamine blockers or stabilizers
Blocking or stabilizing the neurotransmitter dopamine has been shown to reduce chorea. In addition, there is evidence to suggest that normal amounts of dopamine may be toxic in the brain in Huntington's Disease.
Xenazine (tetrabenazine) works as a dopamine depletor and is available inthe U.S. as an FDA-approved treatment for chorea associated with Huntington's disease. It has been available in Europe and Canada for many years.
Glutamate blockers or stabilizers
The excitotoxicity theory holds that neurons are abnormally sensitive to glutamate; overstimulation by this important neurotransmitter can lead to cell death.
Memantine is a glutamate stabilizer that is FDA approved to treat Alzheimer's dementia. Because memantine might also address excitoxicity in HD and because clinical reports from physicians try memantine for HD patients have suggested that it may improve cognitive symptoms, memantine is now in Phase II clinical trials.
Dimebon has several promising mechanisms. In addition to regulating glutamate, it also inhibits acetylcholinesterase and is thought to regulate calcium homeostasis, preventing the pathological opening of the mitochondrial permeability transition pores. Calcium handling is impaired in Huntington's Disease. Following promising results in a phase II trial, Medivation is planning a Phase III trial to be managed by the HSG.
Brain derived neurotrophic factor (BDNF) protects brain cells and promotes neurogenesis, the growth of new ones. Levels of BDNF are known to be reduced in the brains of HD patients. SSRI (selective serotonic reuptake inhibitor) antidepressants are known to elevate BDNF and one such antidepressant, Celexa, is in Phase II clinical trials. In addition, Cortex pharmaceuticals has an ampakine in preclinical testing and Raptor pharmaceuticals is planning Phase II trials of cysteamine; both induce BDNF.
In addition to BDNF, researchers are also looking at other neurotrophic factors and synthetic compounds that mimic their effects with the hope that they will be neuroprotective in HD patients. One candidate is fibroblast growth factor 2 which promoted neurogenesis and extended survival time in the R6/2 mice. It is still in preclinical testing.
Ceregene has developed a viral vector for delivering a gene for the neurotrophic factor neurturin into the brain. This potential treatment is in Phase II clinical trials for Parkinson's Disease and preclinical testing for Huntington's Disease. Trophos has a lead candidate which is neuroprotective in a striatal cell model of HD.
The dysregulation of gene transcription has been shown to be a significant problem in Huntington's Disease. The HD protein interferes with the normal expression of genes. Histone deacetylase inhibitors may be able to reverse or partially reverse this dysfunction. Envivo has a candidate drug which performed well in preformed well in preclinical testing and a Phase I clinical trial is planned for later in 2008. Repligen has licensed an HDAC inhibitor from Scripps Research Institute which reduced pathology and at least partially restored gene transcription.
Huntington's disease is a disease of aging in that cells in the areas of the brain that are affected by HD are for some time able to cope with the challenges presented by the mutant protein. As we age, our cellular defense mechanisms become less efficient. There is a group of genes called sirtuins which appear to regulate aging. In the spring of 2008 Sirtris Pharmaceuticals announced that there is new data showing that in a preclinical model of Huntington's disease, mice live longer and have less disease pathology in the brain with increased SIRT1 expression. Sirtris has several compounds with induce SIRT1 expression.
One problem that increases with aging which is thought to be particularly damaging in HD is oxidative stress. During energy metabolism, free radicals of oxygen are produced which can damage proteins, lipids, and DNA if there aren't enough antioxidants available with which to bond. As mentioned above, creatine and CoQ10 are antioxidants. Intellect Neurosciences is doing preclinical studies with their synthetic version of Indole-3-propionic acid.
The normal huntingtin's protein is cleared away from the cell through the ubuiqitin proteosome system. This housekeeping process is not effective with the HD version of the protein. There is an alternate way to clear away the HD protein called autophagy. Two drugs which are already approved were found to be induce autophagy in cell and drosophila models. The next step is to test these drugs in the HD mice.
Both excess copper and excess iron have been shown to contribute to HD pathology. Pipex Pharmaceuticals, in collaboration with researchers at the VA Medical Center at Ann Arbor, is doing preclinical testing of their copper chelator. Varinel, an Israel Pharmaceutical company is testing their copper chelator in HD mouse models with funding from CHDI.
Research shows that there is an aberrant amplification of the adenosine 2A receptor signaling in striatal cells in people with Huntington's Disease. Kyowa Pharmaceuticals has an A2A receptor antagonist called KW-6002 (istradefyllin) that is in clinical testing for Parkinson's disease.
When an HD mouse model was engineered to be resistant to caspase 6, the HD protein was not cleaved, the protein did not accumulate in the nucleus of the cell, and the mice did not develop Huntington's Disease. CHDI is funding the development of a safe and effective caspase 6 inhibitor.
If the HD gene could be stopped from expressing itself, the result could be a virtual cure. Two pharmaceutical companies, Sirna and Anylam are working on ways to interference with messenger RNA so that instructions to make the HD protein are not sent out. An issue is that it may be necessary to develop allele specific ways to do this so that only the HD protein is shut down and the normal huntingtin's protein continues to be expressed.
The antisense approach being taken by Isis is somewhat different in that it is possible for a drug to do this on a periodic basis; the goal is to find an optimal time in which the cell can recover from the HD protein without being harmed by the absence of the normal protein.
Research with the HD mice suggests that stopping the HD gene from expressing itself would result in improvement even well into the progression of the disease. However, restorative treatments will likely be necessary for full recovery of later stage patients. ReNeuron has a line of stem cells which has shown efficacy in a cell model of HD. Preclinical work is being done.