疾病缓和疗法
已经开展和报告了许多关于潜在改善症状性亨廷顿病基因携带者药物的临床试验，但是没有一项试验证明有临床显著疗效。然而它们证明了在亨廷顿患者群体中开展大型 III 期临床试验的可行性。美国食品药品监督管理局已批准 Deutetrabenazine 用于治疗亨廷顿舞蹈病。这是在 FIRST-HD 和 ARC-HD 研究得出积极的结果之后。[101]Frank S, Stamler D, Sung V, et al. Deutetrabenazine effect on total motor score in patients with Huntington disease (First-HD) (S27.008). Neurology. 2016 Apr 5;86(16 Suppl):S27.008.http://n.neurology.org/content/86/16_Supplement/S27.008[102]Claassen D, Frank S, Stamler D, et al. Rating swallowing function in patients with Huntington disease enrolled in the First-HD study (S25.006). Neurology. 2016 Apr 5;86(16 Suppl):S25.006.http://n.neurology.org/content/86/16_Supplement/S25.006 Deutetrabenazine 是一种囊泡单胺 2 转运体 (VMAT2) 的小分子抑制剂，作用模式与丁苯那嗪相似。拉喹莫德是一种免疫调节剂，先前在多发性硬化中进行过试验。LEGATO-HD 试验旨在研究拉喹莫德的有效性和安全性，目前正在进行中。[103]ClinicalTrials.gov. A clinical study in subjects with Huntington's disease to assess the efficacy and safety of three oral doses of laquinimod (LEGATO-HD). Mar 2018 [internet publication].https://clinicaltrials.gov/ct2/show/NCT02215616 或许对于疾病改善最有希望的疗法是新兴的以 mHTT（亨廷顿突变，mutant huntingtin）基因的 DNA 或 RNA 为靶向降低 mHTT 蛋白。RNA 靶向可通过使用反义寡核苷酸 (ASO)、RNA 干扰 (RNAi)、或小分子剪接抑制剂来实现。ASO 目前正在进行临床试验。在首个人类 Ib/IIa 期的研究中，观察到 ASO 受试者的 mHTT 呈剂量依赖性降低（通过鞘内给药）。此外，ASO 很安全且耐受性良好。[104]University College London. UCL news: drug lowers deadly Huntington's disease protein. Dec 2017 [internet publication].http://www.ucl.ac.uk/news/news-articles/1217/111217-huntingtons-disease-protein
普利多匹定
普利多匹定为多巴胺能稳定剂，已经在 3 个大型 III 期临床试验中进行了研究：MermailHD、[105]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 Dec;10(12):1049-57.http://www.ncbi.nlm.nih.gov/pubmed/22071279?tool=bestpractice.com HART、[106]Huntington Study Group HART Investigators. A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington's disease. Mov Disord. 2013 Sep;28(10):1407-15.http://www.ncbi.nlm.nih.gov/pubmed/23450660?tool=bestpractice.com 以及 Pride-HD。[107]Rodrigues FB, Wild EJ. Clinical trials corner: September 2017. J Huntingtons Dis. 2017;6(3):255-63.https://content.iospress.com/articles/journal-of-huntingtons-disease/jhd170262http://www.ncbi.nlm.nih.gov/pubmed/28968245?tool=bestpractice.com 这些研究均未达到其主要终点 (primary end-points)。开放式前瞻性试验 PRIDE-HD 仍在进行当中。[108]ClinicalTrials.gov. A study evaluating if pridopidine is safe, efficacious, and tolerable in patients with Huntington's disease (Open PRIDE-HD) (NCT02494778). Dec 2017 [internet publication].https://clinicaltrials.gov/ct2/show/NCT02494778
PBT2
PBT2 是一种金属蛋白衰减复合物，可减少金属离子诱导的 mHTT 蛋白聚集。一项 II 期临床试验——Reach2HD 试验显示，PBT2 很安全且耐受性良好，目前 III 期试验计划正在进行中。[109]Huntington Study Group Reach2HD Investigators. Safety, tolerability, and efficacy of PBT2 in Huntington's disease: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015 Jan;14(1):39-47.http://www.ncbi.nlm.nih.gov/pubmed/25467848?tool=bestpractice.com
半胱胺
用于治疗胱氨酸沉积症，半胱胺能够增加脑源性神经营养因子，此生长因子在亨廷顿病患者大脑中被消耗。在一项 3 年的 II/III 期临床试验中，评估了半胱胺对亨廷顿病运动障碍进展的影响。虽然半胱胺很安全且耐受性良好，但其对于运动障碍进展的影响并没有统计学意义。[110]Raptor Pharmaceuticals. News release: Raptor Pharmaceuticals announces phase 2/3 clinical trial results with cysteamine (RP103) in Huntington’s disease. Novato, CA: Raptor Pharmaceuticals, 2014.
Selisistat
去乙酰化酶家族成员之一，可降低 mHTT 蛋白水平。曾在一项 II 期临床试验中研究过这一分子，但并未在统一亨廷顿病评定量表 (UHDRS) 中体现出任何效果。[111]Reilmann R, Squitieri F, Priller J, et al. Safety and tolerability of selisistat for the treatment of Huntington’s disease: results from a randomized, double-blind, placebo-controlled phase II trial (S47.004). Neurology. 2014 Apr 8;82(10 Suppl):S47.004.http://n.neurology.org/content/82/10_Supplement/S47.004
磷酸二酯酶 10A 抑制剂
在纹状体中发现了磷酸二酯酶 10A (PDE10A)，且其水平远在亨廷顿病患者发病前数年就已经开始减少。[112]Niccolini F, Haider S, Reis Marques T, et al. Altered PDE10A expression detectable early before symptomatic onset in Huntington's disease. Brain. 2015 Oct;138(Pt 10):3016-29.https://academic.oup.com/brain/article/138/10/3016/2468706http://www.ncbi.nlm.nih.gov/pubmed/26198591?tool=bestpractice.comPDE10A 抑制剂已被证明可在亨廷顿病动物模型中重建基底神经节回路。[113]Beaumont V, Zhong S, Lin H, et al. Phosphodiesterase 10A inhibition improves cortico-basal ganglia function in Huntington's disease models. Neuron. 2016 Dec 21;92(6):1220-37.http://www.cell.com/neuron/fulltext/S0896-6273(16)30838-8http://www.ncbi.nlm.nih.gov/pubmed/27916455?tool=bestpractice.com一项 II 期临床试验曾研究了 PDE10A 抑制剂 PF-02545920，但并未显示出在运动、认知或行为方面显著的改善。[114]Group HS. Brief report: Pfizer Amaryllis trial ends: negative results lead to termination of extension study. 2016 [internet publication].http://huntingtonstudygroup.org/hd-insights/brief-report-pfizer-amaryllis-trial-ends-negative-results-lead-to-termination-of-extension-study/
