亨丁頓舞蹈症之新治療及展望

The Recent Progress and Perspective of Huntington’s Disease

亨丁頓舞蹈症(Huntington's disease, HD)是一種體染色體顯性遺傳的神經退行性疾病，其特徵包括各種不同的精神症狀、認知能力下降和舞蹈症。亨丁頓舞蹈的致病基因突變是在亨丁頓蛋白(HTT)中編碼麩醯胺酸(glutamine)的三核苷酸(CAG)重複序列擴張。麩醯胺酸擴張導致突變蛋白的結構變化，導致有害功能。細胞內聚集、蛋白質-蛋白質相互作用、泛素-蛋白酶體系統功能障礙、自噬途徑受損、轉錄失調、能量代謝缺陷、線粒體異常、氧化壓力增加、谷氨酸興奮性毒性和神經炎症等都參與了其致病機制。揭示亨丁頓舞蹈症中涉及的許多分子致病機制，其好處為提供潛在的治療標地，而“雞尾酒”方法可能會帶來額外的好處，最終顯著減緩甚至阻止疾病。目前已經有幾種化合物在動物模型中進行了測試，並取得了一些成功，例如營養補充劑或抗氧化劑(coenzyme Q10, creatine, ethyl eicosapentanoic acid)、多巴胺穩定劑(pridopidine)、谷氨酸穩定劑或阻滯劑(remacemide, memantine, and dimebon)，抗凋亡劑(minocycline and ursodeoxycholic acid)、組蛋白脫乙酰酶抑製劑(phenylbutyrate)和BDNF誘導劑(cysteamine and citalopram)。這些化合物已進入臨床試驗，但都沒有成功。其他在動物模型有益但尚待臨床試驗的化合物，是抗氧化劑、抗炎劑、線粒體功能激活劑、組蛋白去乙酰化酶抑製劑、伴蛋白酶體和自噬增強劑、神經營養因子的紋狀體遞送、谷氨酸阻滯劑和磷酸二酯酶 10A (phosphodiesterase 10A, PDE10A)抑製劑。其他潛在的治療策略，如幹細胞療法、RNA干擾、特殊飲食療法和環境豐富也可能是有希望的。最近，目前針對突變HTT DNA和RNA的策略，正在進行臨床試驗，並顯示出治療效果的潛力。

Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disorder, characterized by various psychiatric manifestations, cognitive decline and chorea. The causative gene mutation for HD is an expanded CAG trinucleotide repeat sequence, encoding a polyglutamine (polyQ) tract, in the huntingtin (HTT). The polyQ expansion causes a conformational change in the mutant protein leading to deleterious functions. Several pathogenic processes such as intracellular aggregates, protein-protein interaction, dysfunction of the ubiquitin-proteasome system, impaired autophagy pathway, transcriptional dysregulation, defective energy metabolism, mitochondrial abnormalities, increased oxidative stress, glutamate excitotoxicity, and neuroinflammation are involved in the pathogenesis of HD. The benefit of uncovering many molecular pathogenic mechanisms implicated in HD is that they all provide potential therapeutic targets, and a ‘cocktail’ approach might result in additive benefits ultimately lead to dramatically slowing or even arresting the disease. Several compounds have been tested in animal models with some success, such as nutritional supplements or antioxidants (coenzyme Q10, creatine, ethyl eicosapentanoic acid), dopamine stabilizer (pridopidine), glutamate stabilizers or blockers (remacemide, memantine, and dimebon), anti-apoptotic agents (minocycline and ursodeoxycholic acid), histone deacetylase inhibitors (phenylbutyrate), and BDNF inducers (cysteamine and citalopram). These compounds have been moved into clinical trials, but none has succeeded. Other compounds that have also been beneficial in animal models but await clinical trials are antioxidants, anti-inflammatory agents, mitochondrial function activators, histone deacetylase inhibitors, chaperone-proteasome and autophagy enhancers, instriatal delivery of neurotrophic factors, glutamate blockers, and phosphodiesterase 10A (PDE10A) inhibitor. Other potential therapeutic strategies such as stem cell therapy, RNA interference, special diet therapy and environment enrich may also be promising. More recently, strategies targeting mutant HTT DNA and RNA are now under clinical trials and showing potential in therapeutic effects.