Novel Targets for Huntington's Disease
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Degenerative Neurological and Neuromuscular Disease Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Novel targets for Huntington’s disease: future prospects Sarah L Mason1 Abstract: Huntington’s disease (HD) is an incurable, inherited, progressive, neurodegenerative Roger A Barker1,2 disorder that is characterized by a triad of motor, cognitive, and psychiatric problems. Despite the noticeable increase in therapeutic trials in HD in the last 20 years, there have, to date, been 1John van Geest Centre for Brain Repair, 2Department of Clinical very few significant advances. The main hope for new and emerging therapeutics for HD is to Neuroscience, University of develop a neuroprotective compound capable of slowing down or even stopping the progres- Cambridge, Cambridge, UK sion of the disease and ultimately prevent the subtle early signs from developing into manifest disease. Recently, there has been a noticeable shift away from symptomatic therapies in favor of more mechanistic-based interventions, a change driven by a better understanding of the pathogenesis of this disorder. In this review, we discuss the status of, and supporting evidence for, potential novel treatments of HD that are currently under development or have reached the level of early Phase I/II clinical trials. Keywords: disease modification, transcript dysregulation, glial modulation, cell death Introduction Huntington’s disease (HD) is an incurable, inherited, progressive, neurodegenerative disorder that is characterized by a triad of motor, cognitive, and psychiatric problems,1 although it is now widely recognized that there are clinical features that extend beyond these domains, such as abnormalities in sleep2,3 and metabolism.4 The genetic basis of HD is an unstable CAG expansion within exon 1 of the huntingtin gene, located on the short arm of chromosome 4,5 which leads to the production of abnormal mutant huntingtin (mHtt) that is ubiquitously expressed throughout the human body. As such, the pathology of HD is not exclusively restricted to the brain,6 but is nevertheless most clearly seen at this site, with many structural scanning studies in premanifest gene carriers revealing significant striatal atrophy prior to the onset of clinical features. In some cases, these changes are found a decade or more in advance of patients’ estimated time for disease onset,7–16 and the extent of striatal (especially caudate) atrophy increases as patients approach clinical onset and start to develop motor symptoms and signs.10,15 Of course, changes in a large number of extrastriatal sites have also been reported, in some cases in premanifest patients, Correspondence: Sarah L Mason including atrophy of the globus pallidus,12,14 thalamus,12,16 amygdala,17 and insula,14 John van Geest Centre for Brain Repair, but none shows the same level of correlation with disease onset as those associated ED Adrian Building, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK with striatal volume loss.11 Tel +44 1223 331 160 HD is a relatively rare condition with considerably lower prevalence than many other Fax +44 1223 331 174 Email [email protected] neurodegenerative diseases, such as Alzheimer’s or Parkinson’s disease. Approximately submit your manuscript | www.dovepress.com Degenerative Neurological and Neuromuscular Disease 2016:6 25–36 25 Dovepress © 2016 Mason and Barker. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/ terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the http://dx.doi.org/10.2147/DNND.S83808 work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Mason and Barker Dovepress 2.71 people per 100,000 worldwide18 are affected by the integrity of the frontostriatal circuitry.27 In early disease, the disease, with approximately 30,000 people in the USA and cognitive difficulties experienced by patients tend to be highly 38,000 people in Europe currently living with HD, and a specific with a characteristic pattern of impairment, although further 250,000 people worldwide who are at risk of having the severity of this does vary between individuals or within inherited the mutated gene.19 Numbers appear to be increas- individual families. Cognitive decline is slowly progressive ing, as revealed in a recent study which estimated that more and tends to correlate with the extent of atrophy in cortical28,29 than 5,700 people in the UK over the age of 21 years had and subcortical structures,28 eventually leading to global clinical features of HD in 2010, almost twice as many as that cognitive impairment in most, but not all, cases.30 reported in 1990.20 The reason for this increase is unclear, HD is also associated with a wide range of psychiatric although it is likely to reflect advances in the diagnostic pro- symptoms, including affective disorders, irritability, apathy, cess and the greater availability and improved management of and psychosis.31,32 The exact underlying pathology respon- patients in specialist clinics with subsequently increased life sible for these aspects of the disease is currently unknown. expectancies. The exact prevalence of the disease is hard to As psychiatric symptoms tend to cluster in certain HD determine because despite genetic testing being available in families, even in non-gene-carrying relatives,33,34 it has been most countries, only between 4% and 24% of at-risk individu- suggested that affective changes may be a response to the als choose to be tested for the expansion.21 Social stigma and emotional stress of living in an HD family. However, while the potential for discrimination by both employers and insur- such a relationship may play a part, it is unlikely to be the ance companies probably contribute to the reasons underlying whole explanation. the poor uptake of predictive testing in the UK, along with Recent studies have shown that it is the cognitive and the current lack of disease-modifying therapies and the inade- psychiatric difficulties experienced by patients, and not quacy of information provided by general practitioners.22 the movement disorder, that put the largest burden on HD However, regardless of the reasons, the increased prevalence families, and which are most predictive of the need for of HD results in an increase in the economic burden of the nursing home care.35–37 Therefore, treating these aspects of disease, which is already substantial. It has been estimated the disease, rather than the motor features, may have the that the direct medical costs of a patient with late-stage HD greatest impact on quality of life for both the patient and in the USA is between $22,582 and $37,495 per year, much their carer/family. of which can be attributed to nursing home care costs.23 Given this, new therapeutic options are greatly needed, of both the Existing treatments symptomatic and disease-modifying type. The course of HD is relentless: following disease onset, the clinical features will progress over a course of 20 years Clinical features of HD and will ultimately result in death.38 Despite the noticeable The dominant motor feature of HD is the presence of distinc- increase in HD therapeutic trials in the last 20 years, there tive choreic movements that are relentless during waking have been very few significant breakthroughs.39 Currently, hours, cannot be voluntarily suppressed, and worsen in stress- few high-quality clinical trials have been conducted, although ful situations.24 These are accompanied by problems of gait, this is changing with the establishment of such networks as speech, and swallowing. In the later stages of the disease, the Huntington’s Study Group and the European Huntington’s these choreic features tend to give way to bradykinesia and Disease Network, who liaise directly with industry partners to rigidity, resulting in increased dependence on others, and in ensure the quality and relevance to HD of all new trial proto- the final stages of the disease immobility. In juvenile cases, cols. The majority of drugs presently used in clinical practice more often, the chorea is not seen, and the patients develop are chosen not based on reproducible verifiable evidence, but a progressive parkinsonian state with profound bradykinesia, more on anecdotal clinical experience, with the only empiri- tremor, and myoclonus. cal evidence to support their use coming from case reports Although HD has traditionally been thought of as a or small open-label studies. This is especially the case for movement disorder, cognitive and psychiatric disturbances both the cognitive and psychiatric aspects of the disease. In a are also seen in nearly all cases of HD, begin early in the recent study of European prescription practices, 84% of the course of the disease, and in many cases appear ahead of any registered 2,128 patients with HD were prescribed symptom- overt motor features.25,26 The cognitive impairment in HD is atic treatments, of which 50% were for depression compared classified as a subcortical dementia, typically with cognitive to 28% that received antichoreic medication. Patients were deficits that are consistent with disruption to the functional also commonly treated for irritability and aggression (13%), 26 submit your manuscript | www.dovepress.com Degenerative Neurological and Neuromuscular Disease 2016:6 Dovepress Dovepress Novel Huntington’s targets sleep disturbances (9%), and psychosis (7%), indicating that of intracellular protein-clearance mechanisms, such as nonmotor aspects of the disease represent the major burden autophagy and the ubiquitin–proteasome system.