Curr Neurol Neurosci Rep (2017) 17: 33

DOI 10.1007/s11910-017-0739-9

MOVEMENT DISORDERS (S FOX, SECTION EDITOR)

Huntington’s Disease—Update on Treatments

Kara J. Wyant 1 & Andrew J. Ridder 1 & Praveen Dayalu 1

Published online: 21 March 2017

# Springer Science+Business Media New York 2017

Abstract Huntington’s disease (HD) is an autosomal domi- a trinucleotide repeat expansion in the huntingtin gene (HTT)
nantly inherited neurodegenerative disease characterized by on chromosome 4 [1]. The gene product, huntingtin protein, is
progressive motor, behavioral, and cognitive decline, ending widely expressed and has many functions in human neurons.
in death. Despite the discovery of the underlying genetic mu- In the general population, there is an average of 17–20 CAG
tation more than 20 years ago, treatment remains focused on repeats in the HTT gene. With 40 or more CAG repeats, HD
symptomatic management. Chorea, the most recognizable emerges with 100% penetrance. The typical age of disease
symptom, responds to medication that reduces dopaminergic onset is between 20 and 65 years; the disease progresses in-
neurotransmission. Psychiatric symptoms such as depression exorably over an average of 20 years and is ultimately fatal.
and anxiety may also respond well to symptomatic therapies. Management options at this time are limited, and there is still
Unfortunately, many other symptoms do not respond to cur- no therapy to slow the neurodegeneration or the overall rate of
rent treatments. Furthermore, high-quality evidence for treat- function loss. However, over the past decade, there have been
ment of HD in general remains limited. To date, there has been many more clinical trials for symptomatic and potentially neu-
minimal success with identifying a disease-modifying therapy roprotective treatments. In addition, early human trials of gene
based upon molecular models. However, one of the emerging silencing techniques are now underway. This paper reviews
gene silencing techniques may provide a breakthrough in the current treatment landscape for HD, with an emphasis on
treating this devastating disease. recent clinical trials literature and on future directions.
HD is best understood as a combination of motor, cogni-
Keywords Huntington . Neurodegeneration . Chorea . tive, and psychiatric derangements. We consider each domain
Behavioral . Cognitive . Treatment in turn, summarizing the typical symptomatic manifestations
before exploring relevant treatments and trials.

Introduction
Motor Symptoms
Huntington’s disease (HD) is an autosomal dominant inherited
neurodegenerative disease characterized by progressive mo- Although chorea is only a small part of motor dysfunction in
tor, behavioral, and cognitive decline. The disease results from HD, it is its most recognizable and treatable feature. Chorea
often begins as fleeting, suppressible, random fidgety move-
This article is part of the Topical Collection on Movement Disorders ments, seen best in the distal extremities. With time, chorea
may involve more proximal muscles and even become ballis-
* Kara J. Wyant tic. Severe chorea may result in exhaustion or falls. HD com-
[email protected] prises many other motor phenomena, however. As the disease
advances, chorea can actually “burn out” only to give way to
1
Department of Neurology, University of Michigan, 1324 Taubman
motor phenomena that are more disabling and harder to treat.
Center, SPC 5322, 1500 E. Medical Center Drive, Ann These include bradykinesia (slowness and reduced scaling of
Arbor 48109-5322, USA movement), dystonia (posturing and twisting), rigidity, and
33 Page 2 of 11 Curr Neurol Neurosci Rep (2017) 17: 33

ataxia. Dysphagia contributes to weight loss and aspiration. points on the chorea score was identified between the groups.
Postural instability leads to falls, and serious injuries become Adverse events in this study were notable for one suicide,
increasingly common. Progressive motor failure is a major increased suicidal ideation, and depression [7]. In the open-
cause of life-ending complications. label extension study over 80 weeks, there was a high attrition
rate, with only 45 of 75 participants completing. While signif-
icant chorea benefits were still seen, there was also a subse-
Treatment of Motor Symptoms quent increase in extrapyramidal symptoms including parkin-
sonism and dysphagia (though the latter was generally mild).
Chorea The most common side effect was sedation; but depression,
anxiety, insomnia, and akathisia were also commonly report-
Many patients with chorea are neither aware of, nor impaired ed. Three of the participants withdrew from the study as a
by, the involuntary movements. In these cases, reassurance result of neuropsychiatric symptoms including depression, de-
and education (especially of family members) is important. lusions with associated suicidal behavior, and vocal tics [8].
Chorea only requires treatment when it impairs the patient’s Another long-term study of the efficacy and safety of TBZ
quality of life, function, or safety. followed 68 patients for an average of 3 years. The overall
The predominance of chorea in early HD is explained by effectiveness of TBZ on chorea declined with longitudinal
early preferential loss of striato-GPe neurons, key components follow-up, despite a 60% increase in the mean dose.
of the indirect pathway. This initial dysfunction of the indirect Drowsiness and depression were still the most commonly re-
pathway results in inhibition of the subthalamic nucleus, ported side effects, but overall TBZ was well tolerated with
resulting in a hyperkinetic state [2, 3]. Reducing dopamine only 2 participants withdrawing due to severe side effects [9].
neurotransmission, either via presynaptic depletion or via D2 Kenney et al. also demonstrated that TBZ had long-term tol-
receptor blockade, has the net effect of reducing excessive erability and efficacy in a diverse population with hyperkinet-
movement. This is the key idea behind existing pharmacother- ic movement disorders. In this study, all adverse effects were
apy for chorea. felt to be dose-related and decreased with dose reduction [6].
Tetrabenazine (TBZ) is the only medication currently Discontinuation of TBZ has also been shown to be safe, but
FDA-approved for treatment of chorea in HD. TBZ reversibly might worsen chorea [8, 10]. Another study of 98 patients
inhibits the vesicular monoamine transporter 2 (VMAT-2) in with HD chorea treated with TBZ followed for a mean of
the central nervous system. Since VMAT-2 packages seroto- 3.1 years reported three study participants with suicidal idea-
nin, dopamine, and norepinephrine from the cytoplasm into tion and attempted suicide [11].
presynaptic vesicles, its inhibition leads to premature degra- The above-mentioned results, in conjunction with the
dation of these monoamines [4]. The resulting depletion of known depletion of serotonin and norepinephrine resulting
dopamine reduces chorea, while depletion of serotonin and from TBZ, prompted a black box warning for increased risk
norepinephrine may worsen depression and anxiety. Dosing of depression and suicidality with this drug. While at least one
TBZ can be tricky as some patients respond to small doses and subsequent observational study did not find an increased risk
others to much larger doses. Most of the studies start with in TBZ-exposed patients [12], this drug should be avoided in
12.5 mg per day and up-titrate to a max dose of 300 mg per patients with uncontrolled depression or with a history of
day or less; however, the degree of benefit is usually limited suicidality. We note that depression and suicide are already
by side effects. Because of its short half-life, TBZ is dosed common in the HD population and are often a much bigger
three times a day [5]. TBZ is metabolized hepatically via the problem than the involuntary movements. This, and the ex-
CYP2D6 system, which is induced by fluoxetine and paroxe- treme cost of tetrabenazine in the USA at this time, argue
tine. It is recommended that patients receiving more than against recommending TBZ as the first line for HD chorea.
50 mg of TBZ per day be genotyped for CYP2D6, to enable Recently, a randomized, double-blind, placebo-controlled
dosage adjustments that minimize side effects. However, a trial was published about the effect of deutetrabenazine (SD-
retrospective review questioned the validity of this recommen- 809) on chorea in patients with HD. This is a novel molecule
dation [6]. containing six deuterium atoms, or “heavy hydrogen”, in
The best evidence for safety and efficacy of TBZ for HD- place of typical hydrogen. Deuterium-carbon bonds require
associated chorea is the TETRA-HD study and its open-label more energy for cleavage. This increases the half-life of the
extension. TETRA-HD was the first randomized controlled active metabolite so that fewer and lower doses are needed to
trial (RCT) that showed a benefit for TBZ for HD chorea. obtain the same benefit. The hope is to decrease the unwanted
Eighty-four patients with HD were randomized 2:1 to TBZ side effects of sedation and akathisia that occur at peak doses
or placebo. The primary outcome was change in the Universal and to optimize dosing for control of chorea. The study
Huntington’s Disease Rating Scale (UHDRS) chorea score showed a significant decrease in the UHDRS chorea score
after 12 weeks. A clinically significant mean difference of 5 and UHDRS total motor score in patients taking twice a day
Curr Neurol Neurosci Rep (2017) 17: 33 Page 3 of 11 33

deutetrabenazine when compared to those of placebo. There state-dependent effects on dopamine transmission. When do-
was no increase in depression, suicidal ideation, or sedation paminergic tone is low, dopidines enhance transmission; when
compared to that of placebo [13••]. While it is not surprising tone is high, they antagonize dopamine receptors, similar to
that this molecule could successfully suppress chorea, a head- antipsychotics [29]. The hope is that such drugs might im-
to-head study versus standard TBZ is needed to demonstrate prove other aspects of motor dysfunction in HD, instead of
additional value of the deuterated form; for example, a mean- merely dampening chorea. One such molecule, pridopidine,
ingful decrease in side effects. has been tested with three randomized, double-blind, placebo-
Although TBZ is FDA-approved and has better clinical controlled trials. These studies showed that when dosed at
trial evidence, the risk of depression is a serious concern. 90 mg per day, there may be improvement in motor symptoms
The neuroleptics, while off-label and less supported by trials, of HD, but not necessarily chorea; and there was no statistical
have a long history of use for HD chorea in the USA, and have improvement seen in functional outcomes [30, 31]. There are
the advantage of being adjuncts to treatment of depression and conflicting results regarding this drug’s effect on cognition
behavioral issues which are commonly seen in patients with and behavioral symptoms [29–31]. This medication is well
HD. Antipsychotics have varying affinity for the D2 receptor, tolerated with a side effect profile similar to that of placebo,
and thus vary in their ability to control chorea in patients with except for a potential increased risk of seizures [31]. While the
HD. It is important to recognize that they can all cause extra- antichorea effect is limited, the report of improvement in gait,
pyramidal side effects of parkinsonism, akathisia, and tardive balance, and dystonia is promising, as these are less respon-
movement disorders; as well as non-motor side effects like sive to other drugs. However, larger and more rigorous trials
sedation, QT prolongation, and weight gain (may be benefi- are needed to establish this drug as an advance in HD symp-
cial in some HD patients). tomatic treatment.
The evidence for typical antipsychotics including haloper- Other medications have been evaluated for use in treatment
idol [14, 15], perphenazine [15], pimozide [16], and fluphen- of HD-associated chorea, but results have been disappointing.
azine [17] consists of small, non-randomized studies that Amantadine, an NMDA antagonist with poorly understood
show mixed effect on chorea. The atypical antipsychotics effects at dopaminergic synapses, has antidyskinetic proper-
have similarly poor evidence to support their use in patients ties in Parkinson disease, and thus might be expected to treat
with HD. A double-blind, placebo-controlled study of cloza- chorea in HD. There have been three small, randomized, pla-
pine in 33 patients with HD showed dose-dependent improve- cebo-controlled, crossover trials in addition to one open-label
ment in chorea; but side effects were limiting and led to dose prospective study with varying results. There may be a poten-
reduction and discontinuation in nearly half their participants tially beneficial effect of treatment on hyperkinesia in HD
[18]. A second, much smaller, open-label trial also showed [32–34], but no benefit was seen for cognition or behavior
improvement in chorea, and it was reported as being better [32, 33]. Unfortunately, high doses of amantadine were re-
tolerated [19]. The side effect profile including agranulocyto- quired to attain symptomatic benefit for chorea, leading to
sis and seizures is not favorable; weekly screening blood intolerable side effects including hallucinations, confusion,
draws would be especially impractical in the HD population. insomnia, sleepiness, agitation, and anxiety [34, 35].
Of the other atypical antipsychotics, several small, open-label Riluzole, an antiglutamatergic drug posited to work by allevi-
trials showed a reduction in chorea with olanzapine [20–22]; ating excitotoxicity, also failed to show improvement in cho-
and there is one-blinded, crossover study comparing rea, behavioral and cognitive symptoms, and functional inde-
aripiprazole to TBZ that showed comparable effect on chorea pendence when compared to those of placebo in a large ran-
with less sedation [23]. Risperidone also has case reports to domized 3-year study [36]. The Huntington Study Group
support improvement in involuntary movements and psycho- looked at higher doses of riluzole and found a beneficial effect
sis related to HD [24–26]; the same is true for quetiapine and on chorea in participants receiving 200 mg per day; however,
ziprasidone [27, 28]. this was no longer significant when controlling for neuroleptic
We feel that haloperidol, fluphenazine, risperidone, and use. The most significant adverse effect was a dose-dependent
olanzapine are all reasonable options. We do not recommend elevation in ALT [37].
clozapine and quetiapine for HD chorea, for the same reason The last evidence-based medicine guidelines published in
that they are less likely to worsen parkinsonism, as these drugs 2012 by the American Academy of Neurology for treatment
have the lowest affinity for D2 receptors. There is a stark of chorea in Huntington’s disease cite strong evidence to sup-
absence of head-to-head studies or RCTs to otherwise help port the use of TBZ in patients with HD, and weaker evidence
to guide their use. However, the best advice is to start low, for the use of amantadine and riluzole [38]. As mentioned
and go slow, and switch to a different agent if problems earlier, we have other reasons to favor the use of antipsy-
develop. chotics for HD chorea. If antipsychotics and TBZ are not an
The dopidines are a novel class of “dopamine stabilizers” option or have failed, then we would consider amantadine,
in development. Their complex pharmacodynamics results in followed by riluzole.
33 Page 4 of 11 Curr Neurol Neurosci Rep (2017) 17: 33

Deep brain stimulation (DBS) might be an option for some Given the limited drug treatment options, exercise-based
patients with medically refractory HD chorea. There are now therapies might be of value in HD. Physical therapy (PT)
multiple case reports and series in the literature demonstrating can be very helpful in the earlier stages to evaluate and address
short- and long-term benefit of deep brain stimulation with gait impairment, imbalance, and falls. Occupational therapists
bilateral internal globus pallidi (GPi) stimulation. The major (OT) can assist when motor dysfunction begins to interfere
side effects of stimulation are dystonia and bradykinesia; that with activities of daily living. Therapists and social workers
may result from progression of the underlying disease or as a can recommend assistive devices and home modifications
result of stimulation [39, 40•, 41, 42]. While chorea shows a (e.g., grab bars, shower chairs) to enhance independence and
significant and durable response to DBS, dystonia does not; so safety. In addition to PT and OT for motor symptoms, speech
phenomenology should be carefully evaluated prior to surgery pathologists can help at all stages of the disease process, with
[39, 43, 44]. There are variable reports of functional improve- dysarthria and dysphagia. We recommend speech and swal-
ment, but quality of life seems to improve with treatment [45]. low therapy before the onset of significant dysphagia, so that
In patients with medically intractable chorea with significant behavior and diet can be modified to reduce aspiration risk.
quality-of-life impairment, bilateral GPi DBS may be consid-
ered. However, recommendation for the neurosurgical treat-
ment of HD patients should not be taken lightly. Chorea is the Cognitive Symptoms
predominant phenotype for only part of the disease process,
and over time the bradykinesia and dystonia predominate. Progressive cognitive disturbance is inevitable in HD. A large-
Adequate education about the disease process for the patient scale prospective observational analysis of premanifest per-
and family member cannot be understated given the risks as- sons with HD showed that cognitive impairment can be mea-
sociated with brain surgery, especially in a population where sured before the motor manifestations, and the rate of decline
the target is actively degenerating, and the potential benefit increases as patients near motor onset of their disease [57], and
has a limited duration. eventually progresses to frank dementia. The cognitive effects
of HD are underappreciated, as the dementia is subcortical
with deficits in processing speed, attention, problem-solving,
Other Motor Manifestations and memory retrieval; unlike the more striking defects of
memory encoding, language, and visuospatial dysfunction
HD encompasses many more motor problems than chorea. seen in cortical dementias like Alzheimer’s disease [58].
Unfortunately, treatment options for the rest of the motor dis- Therefore, traditional screening measures such as the
order are limited and based on low-quality evidence. Folstein Mini-Mental State Examination (MMSE) are less
Patients with onset of HD before the age of 20 are more useful in HD. Patients tend to have poor insight into their
likely to present with an akinetic-rigid syndrome known as deficits due to dysfunction of the frontal striatal connections
Westphal variant HD. This presentation is relatively rare in [59], compounding safety concerns and family distress.
adults, but several cases have been reported [46, 47]. In child- Cognitive dysfunction in HD disrupts social and occupational
hood, 65–85% of patients present with this phenotype, and it function in the prime of these patients’ lives, and we lack good
can be seen in up to 55% of those presenting as young adults. treatment options for it at this time.
The predominant phenomenology is parkinsonism with dys-
tonia. Treatment with levodopa [40•, 48, 49] and dopamine
agonists [47, 50, 51] has shown a variable benefit in case Treatment of Cognitive Symptoms
reports. We favor levodopa over dopamine agonists in this
population given the generally higher likelihood of behavioral Despite their use in other dementias, there is little evidence to
side effects with the latter. Surgical management with bilateral support the use of cholinesterase inhibitors or memantine in
GPi pallidotomy and DBS in this population has been tried this population. Of the cholinesterase inhibitors, rivastigmine
with minimal and non-sustained effect [52, 53]. is possibly the best option. There are three small open-label
Cortical myoclonus is another uncommon phenomenon studies which suggest improvement in cognitive testing after
seen in juvenile more than adult onset HD. The myoclonus treatment with short- and long-term treatment with
is stimulus- and action-sensitive; abnormalities may be seen rivastigmine [60–62]. However, there has been criticism of
on EEG. The speculated mechanism is due to deficiency in these studies, because the MMSE is not felt to adequately
GABA, so these patients may respond to valproic acid or capture the impairments in processing speed and frontal dys-
benzodiazepines [54–56]. Dystonia is common in HD, but function that are common in patients with HD. There is one
no trials have assessed its treatment specifically in this con- small, randomized, placebo-controlled trial with more rigor-
text. Botulinum toxin might be useful for patients with severe ous cognitive testing that demonstrated a trend toward im-
or disabling focal or segmental dystonia. provement in the recognition of verbal information in HD
Curr Neurol Neurosci Rep (2017) 17: 33 Page 5 of 11 33

patients on rivastigmine at 6 months [62]. There is even less (REGISTRY) of 1,993 patients, only half of patients reporting
evidence to support the use of donepezil [63]. moderate to severe depression were on medications for their
The striatum receives a massive glutamatergic input from symptoms [70]. Depression is the most common psychiatric
the cortex and thalamus, and thus it is postulated that at least symptom and occurs in 33–70% of patients with HD [70, 71].
part of the neurodegeneration in HD may occur as a result of This is most prevalent as these patients begin to lose indepen-
excitotoxic damage. Memantine is a non-competitive gluta- dence, but then slowly decreases as the disease progresses.
mate receptor antagonist that stabilizes glutamatergic tone A recent systematic review showed a lack of sufficient
[64]. Despite its use in Alzheimer’s dementia, there are no evidence to guide pharmacotherapy of depression in HD
studies designed to assess memantine for cognition in HD. [72]. Three studies suggested a benefit of the SSRIs and the
One small, open-label study suggested a potential neuropro- SNRI venlafaxine in this population. Of the SSRIs, fluoxetine
tective effect following long-term treatment [65]; however, and citalopram showed a trend toward improvement in the
this finding has yet to be replicated. Hamilton Depression Rating Scale (HDRS), despite the sam-
Given the lack of good evidence for any of these drugs, we ples comprising non-depressed individuals [73, 74].
cannot recommend their routine use to enhance cognition in Venlafaxine XR improved depressive symptoms after 4 weeks
HD. Supportive measures, such as providing cues, minimiz- of treatment [75]; however, this study was uncontrolled and of
ing multitasking, and allowing adequate time for cognitive short duration compared to that of typical trials in depression.
tasks, should be emphasized. Despite this lack of published evidence, a common experi-
ence is that HD patients usually respond to standard treat-
ments of depression, notably SSRIs. For refractory depres-
Psychiatric Symptoms sion, atypical antipsychotics including olanzapine [21, 22],
risperidone [76], aripiprazole [23, 77], and clozapine [78]
Psychiatric disease is the third cardinal feature of HD and can have shown benefit in case reports and small open-label case
also be the most bothersome for patients and their families. series. In cases where adherence is an issue, one case series
Dysfunction can manifest as a wide range of disorders from suggests that long-acting injections of risperidone are safe and
depression to psychosis. Depression, OCD, and other prob- may be effective [79]. ECT has also been shown to be effec-
lems with emotion and behavior are likely related to degener- tive in refractory HD depression [80–82].
ation in striatal circuits involving the frontal lobe and ventral Suicidality in the HD population is a serious problem.
anterior and medial dorsal nuclei of the thalamus [66]. Patients with prior or current depression are more likely to
Disinhibition and apathy in particular, might be due to dys- attempt suicide. About 20% of HD patients in a very large
regulation of the medial prefrontal, anterior cingulate, and cohort endorsed suicidal ideation, and the rate of attempted
anterior temporal paralimbic cortices [67]. suicide might be as high as 10% [70, 83]. Compared to those
As seen with cognitive symptoms, behavioral manifesta- of the general population, patients with HD have a 4–8 fold
tions can start before the diagnosis of HD, and are invariably increased risk of completed suicide [84, 85]. This risk in-
present in nearly all patients throughout the course of the creases at motor symptom onset and when independence be-
disease, independent of motor and cognitive symptoms [66]. gins to decline [83]. Risk factors include lack of offspring,
The exact prevalence of psychiatric symptoms is difficult to being single/divorced, living alone, suicide in other family
assess due to the small studies and variable definitions among members, no contact with other individuals with HD, and
studies. As with cognitive symptoms, the behavioral manifes- depression [85]. Anxiety, aggression/irritability, and prior al-
tations of HD become more prominent around the time of cohol abuse are also associated with higher risk of suicidal
clinical diagnosis [68]. However, unlike cognitive symptoms, ideation [86]. As such, aggressive treatment of behavioral
they are more amenable to treatment. It is important to recog- symptoms and support groups should be encouraged especial-
nize and treat behavioral manifestations of the disease, be- ly in patients who are isolated.
cause the presence of psychiatric symptoms has been shown
to be negatively correlated with daily functioning [68, 69]. Other Behavioral Symptoms

Apathy is the lack of motivation with a decrease in goal-

Treatment of Psychiatric Disease directed behavior that is separate from depressive symptoms.
It is most prevalent in the advanced stages of the disease [70].
Depression and Suicide While less common than depression, it has been reported in
about 50% of large cohort studies [66, 71]. There are no
In our experience, depression can be exquisitely responsive to known effective treatments for apathy in HD. Medications
treatment, yet it remains an undertreated component of the that have been tried include bupropion, bromocriptine, and
illness. In a review of the European HD cohort amoxetine, all without significant improvement [87]. As the
33 Page 6 of 11 Curr Neurol Neurosci Rep (2017) 17: 33

disease advances, if chorea is less a problem, we recommend One obstacle is that we do not yet know the most important
considering a reduction in the dose of tetrabenazine or neuro- functions of the huntingtin protein (htt), or exactly how mutant
leptics, as these drugs can blunt motivation. huntingtin protein (mhtt) causes disease. Htt is important in
Obsessive and/or compulsive symptoms can be seen in 10– embryonic development and survival, but after early develop-
50% of patients with HD [71], but information to guide treat- ment, its role is less clear [98]. There is evidence for a role in
ment is only based upon case reports and expert opinion internal cell signaling, prevention of apoptosis, brain-derived
[88–90]. In a survey of HD experts, SSRIs and clomipramine neurotrophic factor (BDNF) production, and intra and inter-
were most frequently mentioned as the first-line therapies. cellular transport [99]. Mhtt is thought to cause damage in HD
Cognitive behavioral therapy was felt to be an option, but only through toxic gain-of-function mechanisms, and there is evi-
for patients with mild or no cognitive dysfunction. For adjunc- dence that it causes transcriptional interference, cytoskeletal
tive therapy, the respondents most favored antipyschotics and disruption, synaptic dysfunction, mitochondrial damage,
mood-stabilizing antiepileptic drugs (AEDs), such as excitotoxicity, accumulation of toxic aggregates, loss of
valproate, carbamazepine, lamotrigine, and topiramate [90]. BDNF, and changes in axonal transport [99, 100]. Several of
Irritability and agitation occur in 38–73% of patients [71], these have already been pursued as targets for disease-
and this wide range has been supported by other studies [66, modifying therapy, with mostly disappointing results and the
70]. Again, at this time, there are only case reports [91] and recent human trials are summarized in Table 1. Neuronal dys-
surveyed expert opinions to guide treatment. In milder cases function and death in HD are likely the end results of a com-
without aggression, education of families and caregivers on plex combination of both gain and loss of these functions
trigger identification and behavioral strategies to avoid out- [100].
bursts is key. In these cases, SSRIs may help. When there is
coexistent impulsivity, aggression, or hypersexuality, then Genetic Approaches
treatment with atypical antipsychotics and mood-stabilizing
AEDs is recommended over that of SSRIs [92]. Mutant huntingtin has so many complex pathologic effects
Psychosis and delusions are less common in HD and have that any single post-translational therapeutic approach, as de-
been reported in 3–11% of patients [71] with a higher preva- scribed, is likely to be insufficient. The most exciting devel-
lence in later stages [70]. Atypical antipsychotics are recom- opments in the search for a disease-modifying treatment are
mended in these patients, but care should be taken to monitor those targeting the abnormal gene itself. Gene silencing tech-
for side effects [25, 93–95] as hypokinesia can intensify later niques are now in active development in HD. These include
in the disease. down regulating or completely turning off transcription or
Finally, cognitive and behavioral features of the dis- preventing translation of the mutant gene. The most promising
ease may respond to a supportive, structured environ- techniques for HD use antisense oligonucleotides or RNA
ment with routines and cues, whether or not medica- interference (RNAi) mechanisms. These could mitigate the
tions are also used. HD affects young families and has disease at the source, suppressing mutant mRNA prior to
a major impact on caregivers, so it is important to rec- translation, reducing expression of the protein. However, it
ognize and address caregiver burden early. Social would be important to spare the normal allele, as wild-type
workers are invaluable in helping these families and in huntingtin has important functions in development and cellu-
identifying resources such as care assistance, respite, lar function, as discussed earlier.
counselors, and financial sources of support. Antisense oligonucleotides (ASOs) are small single-
stranded molecules synthesized with a sequence complimen-
tary to a particular disease-causing pre-messenger RNA
(mRNA) or mRNA. One kind of ASO acts in the nucleus to
Disease-Modifying Therapies in Huntington’s bind pre-mRNAs, activating RNase H, an enzyme which de-
Disease grades the message before it can be processed for translation.
The ASO in this instance is not degraded, but is left free to
Non-genetic Approaches bind subsequent pre-mRNAs. Other techniques involve ASO
binding to mRNA in the cytoplasm and interfering with ribo-
In the 20 plus years since the discovery of the Huntington’s somal translation via steric hindrance and other mechanisms
disease gene, there have been many attempts at disease mod- [112]. Regardless, the idea is straightforward—if production
ification based on likely functions of huntingtin and on theo- of the abnormal protein can be curtailed, neurodegeneration
ries of neuronal injury. Ideas have ranged from metabolic might be slowed or arrested. In HD, it is possible to target an
interventions to protect neurons, to gene silencing therapies. ASO to the CAG repeat, single nucleotide polypmorphisms
There is also an ongoing work looking for genetic modifiers (SNPs), or introns on the pre-mRNA [113, 114•]. Recent stud-
that determine symptom onset [96, 97]. ies using ASO showed reduced mhtt production in human
Curr Neurol Neurosci Rep (2017) 17: 33 Page 7 of 11 33

Table 1 Non-genetic approaches to Huntington’s disease-modifying RNA interference uses small interfering RNA (siRNA) or
treatment trials
micro RNA (miRNA) molecules to target mRNA for degra-
Mechanism Treatments Results dation prior to translation by activating the RNA-silencing
complex and cleaving the target. As these are short sequences,
Decrease Creatine No effect in large human trial they cannot reliably degrade only mutant mRNA. However,
reactive (mitochondrial [101]
oxygen function)
they can target single nucleotide polymorphisms found in
species Coenzyme Q10 No effect in large human trial some Western and European HD populations [123•, 124].
(mitochondrial [102] Combinations of several siRNAs would be needed to selec-
function) tively target mutant htt without those polymorphisms. Single-
PBT2 (prevention of Failed phase II, safe, improved
copper and zinc trials B subscore [103]
stranded RNA (ssRNA) can work in a similar fashion to
aggregation) siRNA and is longer and more stable, but may only work with
Increase mhtt Selistat (SirT1 No cognitive or motor effect, very long CAG repeats (over 100 in mouse models), not found
clearance inhibitor) slowed increase of soluble in human populations. In the YAD128 HD mouse model,
mhtt [104, 105]
intrastriatal injection of an adeno-associated virus vector with
Cysteamine Unpublished human data, trend
(transglutaminase toward slower motor decline
HTT-silencing miRNA produced a 50% reduction in HTT
inhibitor) [106] mRNA and protein, transduced approximately 80% of the
Increase Glatiramer Increased BDNF in mice, striatum, and improved motor performance [125]. A major
BDNF human trials ongoing [107] current limitation of RNAi is that they cannot enter cells in a
Resveratrol Conflicting animal results [99, naked state; hence the need for a viral vector. Currently, the
108, 109] technique requires injection to both striata, and it is uncertain
Decrease Lamotrigine No effect on progression, how far they can diffuse within the living human brain paren-
neuronal symptomatic improvement in
chyma. They are broken down much quicker than ASOs,
excitotoxic- chorea [110]
ity which could reduce the potential for harm, but also require
Riluzole No effect over 3 years [36]
repeated treatments. There have been two human trials using
Mitochondrial Minocycline No effect in futility trial [111]
protection this approach already, for other diseases [126, 127].
Two other approaches of genetic modification have been
proposed but not tested in humans. The first, zinc finger pro-
teins (ZFPs), can be targeted to the CAG repeats in HD sup-
fibroblasts [115, 116] and improved HD-like pathology and pressing its expression. By virtue of the repeat’s proximity to
motor symptoms in mouse models [117–119]. These targeted the 5′ end of the HTT gene, the ZFPs are selective to HTT
both intronic and exonic SNPs that were generally very selec- without cross-suppressing other poly-CAG-containing genes
tive to the mutant allele and had little effect on the wild-type [120]. In R6/2 mouse models, it decreased production of both
htt production. Several of these experiments also noted con- the mutant protein and mRNA by 95 and 78%, respectively
tinued decrease in mhtt production even months after the last [128]. However, this protein would also need to be virally
treatment. delivered into target cells. The other approach uses the rela-
There are potential stumbling blocks. ASOs directed at the tively recent development of CRISPR-Cas 9 to edit out the
HD CAG repeat may suppress other genes with similar re- mutation at the genome level, completely silencing the gene.
peats, especially if the pathogenic allele contains less than However, neither of these approaches have been clinically
40 repeats. Multiple ASOs targeting SNPs would need to be attempted [123•].
used to adequately target the abnormal allele and still would
only cover approximately 80% of patients [113]. Another pos-
sibility is personalized ASOs based on the patient’s specific
mutation and SNPs, although an FDA protocol for this type of Conclusions
personalized treatment is not fully in place. Additionally,
ASOs do not cross the blood-brain barrier in their current Despite the discovery of the underlying genetic mutation of
formulations and need to be administered intrathecally. They Huntington’s disease more than 20 years ago, we are still
do enter the neurons and their nuclei without a vector [98, limited to treatments that only address the symptoms and not
113]; but it is uncertain how much can reach the human stri- the illness. Furthermore, existing symptomatic therapies are
atum if given via lumbar puncture [120]. There is precedent woefully insufficient. Chorea clearly responds to drug therapy,
for this delivery method in humans for SOD1-associated ALS but other motor problems do not. Some psychiatric symptoms
[121]. There is an ongoing early phase trial of an intrathecal respond well to drug therapy, but dementia does not. There are
htt-directed ASO by Ionis pharmaceuticals that has not report- many promising avenues to treatment on the horizon, such as
ed results yet [122]. gene silencing techniques. Hopefully, within the next 20 years,
33 Page 8 of 11 Curr Neurol Neurosci Rep (2017) 17: 33

we will have discovered an effective way to modify or cure prolong the half-life of TBZ and decrease the side effects.
This new medication could potentially allow for better control
this devastating illness.
of chorea with fewer side effects
14. Leonard DP, et al. Letter: double-blind trial of lithium carbonate
Compliance with Ethical Standards and haloperidol in Huntington’s chorea. Lancet. 1974;2(7890):
1208–9.
Conflict of Interest Andrew J. Ridder declares no conflict of interest. 15. Shoulson I. Huntington disease: functional capacities in patients
Kara J. Wyant has received an educational grant supplying travel and treated with neuroleptic and antidepressant drugs. Neurology.
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Praveen Dayalu is a member and site investigator for the Huntington 16. Arena R, et al. Huntington’s disease: clinical effects of a short-
Study Group (HSG). term treatment with pimozide. Adv Biochem Psychopharmacol.
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Human and Animal Rights and Informed Consent This article does 17. Terrence CF. Fluphenazine decanoate in the treatment of chorea: a
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