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Among the most promising is reducing expression of mutant huntingtin protein (mHTT) with RNA interference or antisense oligonucleotides; human trials are now being planned. Zinc\u2010finger transcriptional repression is another innovative method to reduce mHTT expression. Modulation of mHTT phosphorylation, chaperone upregulation, and autophagy enhancement represent attempts to alter cellular homeostasis to favor removal of mHTT. Inhibition of histone deacetylases (HDACs) remains of interest; recent work affirms HDAC4 as a target but questions the assumed centrality of its catalytic activity in HD. Phosphodiesterase inhibition, aimed at restoring synaptic function, has progressed rapidly to human trials. Deranged cellular signaling provides several tractable targets, but specificity and complexity are challenges. Restoring neurotrophic support in HD remains a key potential therapeutic approach. with several approaches being pursued, including brain\u2010derived neurotrophic factor (BDNF) mimesis through tyrosine receptor kinase B (TrkB) agonism and monoclonal antibodies. An increasing understanding of the role of glial cells in HD has led to several new therapeutic avenues, including kynurenine monooxygenase inhibition, immunomodulation by laquinimod, CB2 agonism, and others. The complex metabolic derangements in HD remain under study, but no clear therapeutic strategy has yet emerged. We conclude that many exciting therapeutics are progressing through the development pipeline, and combining a better understanding of HD biology in human patients, with concerted medicinal chemistry efforts, will be crucial for bringing about an era of effective therapies. \u00a9 2014 The Authors. <jats:italic>Movement<\/jats:italic> Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.<\/jats:p>","DOI":"10.1002\/mds.26007","type":"journal-article","created":{"date-parts":[[2014,8,25]],"date-time":"2014-08-25T09:48:59Z","timestamp":1408960139000},"page":"1434-1445","source":"Crossref","is-referenced-by-count":121,"title":["Targets for future clinical trials in Huntington's disease: What's in the pipeline?"],"prefix":"10.1002","volume":"29","author":[{"given":"Edward J.","family":"Wild","sequence":"first","affiliation":[{"name":"Department of Neurodegenerative Disease UCL Institute of Neurology, National Hospital for Neurology &amp; Neurosurgery Queen Square London WC1N 3BG UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J.","family":"Tabrizi","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease UCL Institute of Neurology, National Hospital for Neurology &amp; Neurosurgery Queen Square London WC1N 3BG UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,8,25]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(10)70245-3"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2014.04.005"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1206506109"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.010909.105654"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-013-1288-1"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0501507102"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2011.201"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2013.200"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.05.009"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.06.001"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcibr1209595"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(13)70061-9"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90542-1"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/81593"},{"key":"e_1_2_14_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1161"},{"key":"e_1_2_14_17_1","doi-asserted-by":"publisher","DOI":"10.2174\/156652311796150354"},{"key":"e_1_2_14_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2011.185"},{"key":"e_1_2_14_19_1","doi-asserted-by":"publisher","DOI":"10.1517\/14712598.2013.774366"},{"key":"e_1_2_14_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2011.219"},{"key":"e_1_2_14_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr333"},{"key":"e_1_2_14_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2011.11.020"},{"key":"e_1_2_14_23_1","unstructured":"BennettCF. 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