Management of Huntington’s Disease – where are we at?

4th January 2019, Dr Chee L Khoo

Huntington Disease (HD) was first described in 1872 by George Huntington, MD, in his paper “On Chorea”. HD is an autosomal-dominant, neurodegenerative disorder that is caused by expansion of a cytosine-adenine-guanine (CAG) triplet repeat in the huntingtin gene which is located on the short arm of chromosome 4 (1). The gene codes for the huntingtin protein. In normal huntingtin, the number of CAG repeats ranges from 6 to 35, whereas with individuals with the dominant HD mutation, the repeat length varies from 36 to 121. Up to 10% of HD are due to new mutation (2).

Since the discovery of the huntingtin gene in 1993 by an international collaborative effort led by the Hereditary Disease Foundation, our understanding of the pathophysiology of the neuronal cell damage and loss in HD has increased dramatically (3). The normal functions of huntingtin have not been completely elucidated although it has been found to play a role in myriad normal processes including axonal and vesicular transport, endocytosis, post-synaptic signalling, and cell survival pathways. Mutant huntingtin (mHtt) undergoes N-terminal cleavage resulting in polyglutamine fragments, which can oligomerise and form aggregates, both cytoplasmic, and nuclear. It is these N-terminal fragments, oligomers of these fragments, and the fully formed inclusions that are thought to be responsible for the toxicity in HD. The toxicity affects a multitude of intracellular processes and causes widespread disruption, including:

• Mitochondrial dysfunction
• Transcriptional dysregulation of various genes
• Altered axonal transport of critical factors
• Disrupted calcium signaling
• Abnormal protein interactions
• Alterations in proteosomal function
• Autophagy

The overall effects of mHtt expression are cell loss and gliosis in the brain, the most prominent of which is in the caudate nucleus and putamen (which together comprise the corpus striatum portion of the basal ganglia).

Although the hallmark of HD is the chorea (uncontrolled movements) that we all remember, the earliest symptoms are often subtle problems with moods and mental abilities. The clinical manifestations of HD comprise motor, cognitive and behavioural components. See Table 1 for the full manifestations.

Table 1. Clinical Manifestations of Huntington Disease

Symptoms usually begin between 30-50 years of age although it can start at any age. With disease progression, patients experience functional decline, increasing disability, loss of independence, and premature death within 15–20 years of symptom onset.

Only two drugs (tetrabenazine and deutetrabenazine) are specifically approved for the management of involuntary choreatic movements in patients with Huntington’s disease. Thus far, no treatment options exist for modification of voluntary motor coordination, worsening function, or disease progression. There are several promising, safe and well tolerated compounds being trialled for amelioration of motor and neuropsychiatric symptoms of HD. However, their efficacy is yet to be proven in clinical trials.

Various hypotheses suggest that disturbances of dopamine metabolism might be the main cause of involuntary movements in HD patients [4]. Hyperkinetic movements result from elevated dopamine concentrations in certain brain areas. Dopamine depletion in other brain areas induces bradykinesia and rigidity (5).

Pridopidine is a dopamine stabiliser, regulating dopamine-dependent behaviours and thus mediating striatal pathways involved in motor control via dopamine type 2 receptors (6). It is hypothesised that it might be useful for treating the hyperactive as well as the hypoactive dopaminergic states in HD. Pridopidine also exhibited high affinity for the sigma-1 receptor chaperone protein, a molecule that is believed to modify multiple pathways known to be impaired in Huntington’s disease and other neurodegenerative diseases.

Two large randomised controlled studies, MermaiHD (7) and HART (8), investigated the effects of pridopidine on motor impairment in patients with Huntington’s disease. It was well tolerated and showed a small improvement in motor score in both studies but was not statistically significant overall. Encouraged by the safety profile, a higher dose of the drug was used in PRIDE-HD trial (9). It reported last month in the Lancet Neurology. Higher dose of pridopidine however, also did not lead to any improvement in the primary endpoint, improvement in voluntary motor function.

While the latest trial results may spell the end of pridopidine as a useful drug in HD, a lot of other experimental and clinical research is under way in HD. The research focus is not only on symptomatic improvement of involuntary movements, but also amelioration of neuropsychiatric features, such as disturbances of cognition and mood. In addition to the usual agents available for depression and psychosis, new treatment concepts are trialled. SRX246 (selective anti-diuretic hormone (ADH) receptor antagonist), bupropion (selective dopamine and noradrenalin reuptake inhibitor) and atomoxetine  (noradrenalin reuptake inhibitor used in ADHD) have been trialled. Some have failed while others have yet to report.

Predictive genetic testing allows an earlier identification of individuals, who will get HD in the further course of their life. This opens the possibility of disease modifying agents that prevent or delay conversion of carriers to active disease. These are agents looking at reducing gene acetylation by histones (thereby reducing damage), agents aimed at reducing neuronal apoptosis, antibodies targeting specific monocytes known to damage neurons, agents that blocked the expression of the mHtt gene and agents that prevent aggregation of the mHtt protein in neurons (10).

Exciting times ahead.

References:

1. Walker FO. Huntington’s disease. Lancet 2007; 369: 218–
2. Dayalu P, Albin RL (February 2015). “Huntington disease: pathogenesis and treatment”. Neurologic Clinics. 33 (1): 101–14. doi:1016/j.ncl.2014.09.003. PMID25432725.
3. https://en.wikipedi0.org/wiki/Hereditary_Disease_Foundation
4. Kumar A, Kumar SS, Kumar V, et al. Huntington’s disease: an update of therapeutic strategies. Gene. 2015;556(2):91–97.
5. Schwab LC, Garas SN, Drouin-Ouellet J, et al. Dopamine and Huntington’s disease. Expert Rev Neurother. 2015;15(4):445–458.
6. Waters S, Tedroff J, Ponten H, Klamer D, Sonesson C, Waters N. Pridopidine: overview of pharmacology and rationale for its use in Huntington’s disease. J Huntingtons Dis 2018; 7: 1–
7. de Yebenes JG, Landwehrmeyer B, Squitieri F, et al. Pridopidine for the treatment of motor function in patients with Huntington’s disease (MermaiHD): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2011; 10: 1049–
8. Huntington Study Group. A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington’s disease. Mov Disord 2013; 28: 1407–
9. Ralf Reilmann*, Andrew McGarry*, Igor D Grachev, Safety and efficacy of pridopidine in patients with Huntington’s disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study. Lancet Neurol December 15, 2018 http://dx.doi.org/10.1016/ S1474-4422(18)30391-0
10. Thomas Müller (2017) Investigational agents for the management of Huntington’s disease, Expert Opinion on Investigational Drugs, 26:2, 175-185 DOI:10.1080/13543784.2017.1270266