Title

亨丁頓舞蹈症之新治療及展望

Translated Titles

The Recent Progress and Perspective of Huntington's Disease

DOI

10.6320/FJM.202207_26(4).0005

Authors

陳瓊美(Chiung-Mei Chen)

Key Words

亨丁頓舞蹈症 ; 新治療 ; Huntington's disease ; potential therapy

PublicationName

台灣醫學

Volume or Term/Year and Month of Publication

26卷4期(2022 / 07 / 25)

Page #

423 - 427

Content Language

繁體中文

Chinese Abstract

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。

English Abstract

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.

Topic Category 醫藥衛生 > 醫藥衛生綜合
Reference
  1. Ross CA, Tabrizi SJ. Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 2011;10:83-98. doi: 10.1016/S1474-4422(10)70245-3
    連結:
  2. Poon LH, Kang GA, Lee AJ. Role of tetrabenazine for Huntington's disease-associated chorea. Ann Pharmacother 2010;44:1080-9. doi: 10.1345/aph.1M582
    連結:
  3. Dean M, Sung VW. Review of deutetrabenazine: a novel treatment for chorea associated with Huntington's disease. Drug Des Devel Ther 2018;12:313-9. doi: 10.2147/DDDT.S138828
    連結:
  4. Pan L, Feigin A. Huntington's disease: New frontiers in therapeutics. Curr Neurol Neurosci Rep 2021;21:10. doi: 10.1007/s11910-021-01093-3
    連結:
  5. Steffan JS, Bodai L, Pallos J, et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 2001;413:739-43. doi: 10.1038/35099568
    連結:
  6. Verny C, Bachoud-Lévi AC, Durr A, et al. A randomized, double-blind, placebo-controlled trial evaluating cysteamine in Huntington's disease. Mov Disord 2017;32:932-6. doi: 10.1002/mds.27010
    連結:
  7. Sack GH Jr. Mitochondrial matters in Huntington disease. J Bioenerg Biomembr 2010;42:189-91. doi: 10.1007/s10863-010-9291-x
    連結:
  8. Liu J, Wang LN. Mitochondrial enhancement for neurodegenerative movement disorders: a systematic review of trials involving creatine, coenzyme Q10, idebenone and mitoquinone. CNS Drugs 2014;28:63-8. doi: 10.1007/s40263-013-0124-4
    連結:
  9. Rodrigues FB, Quinn L, Wild EJ. Huntington's disease clinical trials corner: January 2019. J Huntingtons Dis 2019;8:115-25. doi: 10.3233/JHD-190001
    連結:
  10. Kieburtz K, McDermott MP, Voss TS, et al. A randomized, placebo-controlled trial of latrepirdine in Huntington disease. Arch Neurol 2010;67:154-60. doi: 10.1001/archneurol.2009.334
    連結:
  11. Sharma R, Long A, Gilmer JF. Advances in bile acid medicinal chemistry. Curr Med Chem 2011;18:4029-52. doi: 10.2174/092986711796957266
    連結:
  12. Shannon KM. Pridopidine for the treatment of Huntington's disease. Expert Opin Investig Drugs 2016;25:485-92. doi: 10.1517/13543784.2016.1153627
    連結:
  13. Rusmini P, Cortese K, Crippa V, et al. Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration. Autophagy 2019;15:631-51. doi: 10.1080/15548627.2018.1535292
    連結:
  14. Tabrizi SJ, Ghosh R, Leavitt BR. Huntingtin lowering strategies for disease modification in Huntington's disease. Neuron 2019;101:801-19. doi: 10.1016/j.neuron.2019.01.039
    連結:
  15. Leavitt BR, Kordasiewicz HB, Schobel SA. Huntingtin-lowering therapies for Huntington disease: A review of the evidence of potential benefits and risks. JAMA Neurol 2020;77:764-72. doi: 10.1001/jamaneurol.2020.0299
    連結:
  16. Aslesh T, Yokota T. Development of antisense oligonucleotide gapmers for the treatment of Huntington's disease. Methods Mol Biol 2020;2176:57-67. doi: 10.1007/978-1-0716-0771-8_4
    連結:
  17. Liu CR, Chang CR, Chern Y, et al. Spt4 is selectively required for transcription of extended trinucleotide repeats. Cell 2012;148:690-701. doi: 10.1016/j.cell.2011.12.032
    連結:
  18. Fusco FR, Paldino E. Role of phosphodiesterases in Huntington's disease. Adv Neurobiol 2017;17:285-304.