Treatment and Disease Management

Current Drug Treatments

The treatment of Huntington’s Disease is very limited, and little headway has been made in medical treatment since the mutation was identified in 1993. (Walker 2007) The lack of substantial progress in this area is due to the fact that the mechanism by which truncated mutant huntingtin is toxic to the cell, through interference with nuclear and cytoplasmic protein, is not completely understood. It is also very difficult to control the epigenetic dysregulation that develops in Huntington’s Disease patients. The limited understanding of the epigenetic dysregulation makes drug treatment for Huntington’s difficult. Given that Huntingtin displays increased expression in the striatal cells of the brain, attempts to correct the regulatory mechanisms that lead to striatal cell damage can also have adverse effects on the epigenetic regulation of genes in other tissue. (Walker 2007)

Currently there are no pharmacological treatments that can prevent or slow the course of the Huntington’s disease. However, some drug therapies have been shown to at least improve the symptom’s during onset and progression of HD. One of the main symptoms of Huntington’s, chorea, has been ameliorated by reducing nervous cell functionality with the use of neuroleptics. Some neuroleptics, such as risperidone and tetrabenzine, reduce the involuntary muscle movements of chorea but increase the risk of depression, and thus carefully prescribed (often prescribed with antidepressants) to HD patients because ideas of suicide increases as Huntington’s disease progresses. (Sturrock and Leavitt 2010) Two other pharmacological therapies that have started human clinical trials include Coenzyme Q10 and Creatine. Coenyme Q10 has shown great promise in improving mitochondrial function and reducing oxidative stress  associated with the disease state of Huntington’s Disease. (Sturrock and Leavitt 2010; Walker 2007)


Figure 1: Top Table is a list of drug treatments for Huntington’s that have been tested using HD model mice. Bottom Table is a list drug treatments that have been or are currently being tested on humans. Obtained from: Walker, Francis O. 2007. “Huntington’s Disease.” The Lancet 369 (9557): 218–28. doi:10.1016/S0140-6736(07)60111-1

Potential Treatments and Drug Targets         

As current therapies are very limited as shown in Figure 1, the studies using HD model mice has greatly increased the number drug candidates and drug targets in recent years (Walker 2007). Some of the recent studies in HD model mice have revealed that glutathione peroxidase is neuroprotective, and HDAC inhibitors that can ameliorate the epigenetic dysregulation caused by mHtt. (Mason et al. 2013; Jia et al. 2016) Glutathione peroxidase has anti-oxidative role of catalyzing the reduction of hydrogen peroxide which reduces oxidative stress on the cell. Gluathione peroxidase was found to improve the disease state of Huntingtin’s Disease in mammalian cells without reducing the cells ability to get rid of mutant Huntingtin through autophagy, a process inhibited by other antioxidants. (Mason et al. 2013)

HDAC is a target of huntingtin, and evidence shows that mutant huntingtin increases HDAC activity. HDAC or histone deacetylase reduces the acetyl groups on histones, effectively reducing transcription of certain genes. (Valor 2015) Mutant huntingtin increases HDAC activity subsequently leading to an under expression of certain genes because they cannot be transcribed. HDAC inhibitors slow activity of HDAC, essentially countering the effect of mutant huntingtin. HDAC inhibitors have been shown to ameliorate the disease state of Huntington’s and are continued to be studied as potential drugs. (Jia et al. 2016; Valor 2015)

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Figure 2: Potential chromatin- and non-chromatin-related mechanisms of HDAC1/HDAC3-targeting inhibitors in the context of Huntington’s disease. Different mechanisms associated with inhibition of HDAC1 and HDAC3 enzymes can lead to lowered mutant huntingtin (mHtt) levels, neuroprotective effects or anti-inflammatory effects, all of which can contribute to the improved disease phenotypes observed in HD model systems. Figure obtained from: Thomas, Elizabeth A. 2014. “Involvement of HDAC1 and HDAC3 in the Pathology of Polyglutamine Disorders: Therapeutic Implications for Selective HDAC1/HDAC3 Inhibitors.” Pharmaceuticals 7 (6): 634–61. doi:10.3390/ph7060634

6 Replies to “Treatment and Disease Management”

  1. Hello Zachary,
    I thought you did a great job explaining such a complicated disease!
    I have some quick questions about Huntington’s. The diseased state is having >36 CAG repeats; in your research, did you find anything to suggest that a greater number of CAG repeats past 36 is correlated with more severe symptoms? I realize making such an objective observation is likely difficult.
    Do you happen to know if any neuroplasticity takes effect after the disease begins? Possibly to improve the symptoms?
    Lastly, and along similar lines, are you aware of any sort of therapy – physical therapy or otherwise – that can help patients cope with their chorea?


    1. Thanks and great questions. Yes, increased severity of symptoms and earlier onset of symptoms is associated with increasing number of CAG repeats among most PolyQ disorders. (Walker 2007) There is evidence, using mouse models, that Huntington’s Disease cause abnormalities in short-term and long-term plascticty. (Cummings 2006) Chorea is best managed using drug treatments, however physical therapy can be helpful whn dealing with voluntary movement disorders such as gait. (Sturrock and Leavitt 2010; Walker 2007)

      Cummings, Damian M., Austen J. Milnerwood, Glenn M. Dallérac, Verina Waights, Jacki Y. Brown, Sarat C. Vatsavayai, Mark C. Hirst, and Kerry PSJ Murphy. “Aberrant cortical synaptic plasticity and dopaminergic dysfunction in a mouse model of Huntington’s disease.” Human molecular genetics 15, no. 19 (2006): 2856-2868.

  2. Hi Zachary, you did a great job explaining some very complicated aspects of HD. I have a few questions regarding potential treatments. The figure on a previous page mentions that anthracyclines, a class of chemotherapeutic agents, can block one of the proteins misregulated by mHtt responsible for histone methylation. Has any work specifically been done to see if this is a potential treatment pathway? It doesn’t seem likely as this would address only one small component of an entire misregulated network, but it may be interesting none the less. Along similar lines, do HD patients who have been previously treated with such agents have different outcomes than cancer naive HD patients? And lastly, has any research looked into using the CRISPR/Cas9 system to change the number of repeats in affected patients?


  3. Great work Zach! I found the history and metabolic context page particularly interesting! My question is about HDAC. You mention that HDAC reduces the acetyl groups on histones, thereby reducing transcription, and that mHtt exacerbates this by increasing HDAC activity. However, in Figure 2, the caption states that inhibition of HDAC enzymes can lower mHtt levels. Is the mutant causing an increase in HDAC activity, which also causes an increase in mHtt levels, therefore making it a cycle? I just want to clarify! If this is the case, then will other treatments for HD that lover mHtt levels lower HDAC activity?

    1. Thanks and great question. HDAC activity increase mHtt levels by decreasing the rate by which mHtt is cleared from the cell. Acetylation of mHtt is associated with increased clearance of mHtt by autophagosomes. HDAC1 and HDA3 have been shown to decrease the acetylation of mHtt, so an HDAC inhibitor increases acetylation and subsequently increases clearance of mHTT. (Thomas 2014) A cycle would occur, but only at the point in which the cell becomes slower at degrading and clearing mHtt, allowing aggregates to build up. Yes, treatments that lower mHtt would also lower HDAC activity (Thomas 2014)

  4. Hello Zach!
    I really enjoyed your selection of Huntington’s Disease. HD is a classic disease with such devastating impact on the body. I figured your figure on the title page which showed the normal patient vs the HD patient and how their body functions differ as a result. Since the average age HD appears in between 30 and 40, does there exist any treatments prior to HD onset that can be administered to patients with mHTT in order to reduce the impact of the disease? Is there any method or treatment regimen you found which can prevent HD onset if begun at an early enough age?
    Great work, Zach!
    Tyler Florio

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