Title

遺傳性脊髓小腦萎縮症之新治療

Translated Titles

Developing Treatment for Inherited Spinocerebellar Ataxia

DOI

10.6320/FJM.202207_26(4).0008

Authors

張國軒(Kuo-Hsuan Chang)

Key Words

聚谷氨醯胺 ; 脊髓小腦萎縮症 ; 三核苷酸重複序列 ; RNA干擾 ; 反義寡核苷酸 ; polyglutamine ; spinocerebellar ataxia ; trinucleotide repeat ; RNA interference ; antisense oligonucleotide

PublicationName

台灣醫學

Volume or Term/Year and Month of Publication

26卷4期(2022 / 07 / 25)

Page #

440 - 447

Content Language

繁體中文

Chinese Abstract

脊髓小腦萎縮症(spinocerebellar ataxia, SCA)是一群自體顯性遺傳的神經退化性疾病,由各個獨特致病基因編碼區域CAG三核苷酸重複序列擴增引起,這些帶有重複序列的基因會轉譯為帶有聚谷氨醯胺(polyglutamine)的蛋白。常見的SCA包括六型:SCA1、SCA2、SCA3、SCA6、SCA7、SCA17。這些疾病的典型特徵包含進行性共濟失調(ataxia)、言語障礙、吞咽困難、肢體協調、步態和運動功能障礙。脊髓小腦萎縮症具有神經細胞內聚集的病理特徵,並有許多共通的致病機制,例如內質網壓力、粒腺體功能障礙與氧化壓力、蛋白酶體與細胞自噬功能障礙、伴護蛋白降低、鈣離子失調、神經炎症、轉錄錯誤與RNA毒性等。目前,尚無治療方法可以減緩或阻止疾病進展。本文將回顧脊髓小腦萎縮症的臨床和分子生物機轉,並探討正在開發的RNA干擾(RNA interference)與反義寡核苷酸(antisense oligonucleotide)療法,這些治療未來有可能會進入臨床試驗,成為脊髓小腦萎縮症的新治療方法。

English Abstract

Spinocerebellar ataxia (SCA) is a group of auto-dominant neurodegenerative diseases caused by the expansion of CAG trinucleotide repeats in the coding region of each unique pathogenic gene, which is further transplanted into a protein with a polyglutamine tract. There are six common types of SCA, including SCA1, SCA2, SCA3, SCA6, SCA7 and SCA17. Typical features of SCA include progressive ataxia, speech impairment, dysphagia, limb incoordination, gait and motor dysfunction. SCAs are pathologically characterized by intraneuronal aggregation and could share common pathogenic mechanisms, such as endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress, proteasome and autophagy dysfunction, reduced chaperones, calcium dysregulation, neuroinflammation, transcription dysregulation and RNA toxicity. Currently, there are no treatments to slow or stop disease progression. This article will review the clinical and molecular mechanisms of SCA, and discuss ongoing RNA interference and antisense oligonucleotide therapies that may enter clinical trials in the future as new treatments for SCA.

Topic Category 醫藥衛生 > 醫藥衛生綜合
Reference
  1. Buijsen RAM, Toonen LJA, Gardiner SL, et al. Genetics, mechanisms, and therapeutic progress in polyglutamine spinocerebellar ataxias. Neurotherapeutics 2019;16:263-86. doi: 10.1007/s13311-018-00696-y
    連結:
  2. Du YC, Ma Y, Shao YR, et al. Factors associated with intergenerational Instability of ATXN3 CAG repeat and genetic anticipation in Chinese patients with spinocerebellar ataxia type 3. Cerebellum 2020;19:902-6. doi: 10.1007/s12311-020-01167-x
    連結:
  3. Kang S, Hong S. Molecular pathogenesis of spinocerebellar ataxia type 1 disease. Mol Cells 2009;27:621-7. doi: 10.1007/s10059-009-0095-y
    連結:
  4. Soong BW, Lu YC, Choo KB, et al. Frequency analysis of autosomal dominant cerebellar ataxias in Taiwanese patients and clinical and molecular characterization of spinocerebellar ataxia type 6. Arch Neurol 2001;58:1105-9. doi: 10.1001/archneur.58.7.1105
    連結:
  5. Petruska J, Hartenstine MJ, Goodman MF. Analysis of strand slippage in DNA polymerase expansions of CAG/CTG triplet repeats associated with neurodegenerative disease. J Biol Chem 1998;273:5204-10. doi: 10.1074/jbc.273.9.5204
    連結:
  6. Zoghbi HY, Orr HT. Polyglutamine diseases: protein cleavage and aggregation. Curr Opin Neurobiol 1999;9:566-70. doi: 10.1016/S0959-4388(99)00013-6
    連結:
  7. Sweeney P, Park H, Baumann M, et al. Protein misfolding in neurodegenerative diseases: implications and strategies. Transl Neurodegener 2017;6:6. doi: 10.1186/s40035-017-0077-5
    連結:
  8. Szegezdi E, Logue SE, Gorman AM, et al: Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 2006;7:880-5. doi: 10.1038/sj.embor.7400779
    連結:
  9. Hubener J, Vauti F, Funke C, et al. N-terminal ataxin-3 causes neurological symptoms with inclusions, endoplasmic reticulum stress and ribosomal dislocation. Brain 2011;134:1925-42. doi: 10.1093/brain/awr118
    連結:
  10. Scheper W, Hoozemans JJ. The unfolded protein response in neurodegenerative diseases: a neuropathological perspective. Acta Neuropathol 2015;130:315-31. doi: 10.1007/s00401-015-1462-8
    連結:
  11. Hsu JY, Jhang YL, Cheng PH, et al. The truncated C-terminal fragment of mutant ATXN3 disrupts mitochondria dynamics in spinocerebellar ataxia type 3 models. Front Mol Neurosci 2017;10:196. doi: 10.3389/fnmol.2017.00196
    連結:
  12. Ito H, Fujita K, Tagawa K, et al. HMGB1 facilitates repair of mitochondrial DNA damage and extends the lifespan of mutant ataxin-1 knock-in mice. EMBO Mol Med 2015;7:78-101. doi: 10.15252/emmm.201404392
    連結:
  13. Torres-Ramos Y, Montoya-Estrada A, Cisneros B, et al. Oxidative stress in spinocerebellar ataxia type 7 is associated with disease severity. Cerebellum 2018;17:601-9. doi: 10.1007/s12311-018-0947-0
    連結:
  14. de Assis AM, Saute JAM, Longoni A, et al. Peripheral oxidative stress biomarkers in spinocerebellar ataxia type 3/Machado-Joseph disease. Front Neurol 2017;8:485. doi: 10.3389/fneur.2017.00485
    連結:
  15. Chang KH, Chen WL, Wu YR, et al. Aqueous extract of Gardenia jasminoides targeting oxidative stress to reduce polyQ aggregation in cell models of spinocerebellar ataxia 3. Neuropharmacology 2014;81:166-75. doi: 10.1016/j.neuropharm.2014.01.032
    連結:
  16. Chen CM, Weng YT, Chen WL, et al. Aqueous extract of Glycyrrhiza inflata inhibits aggregation by upregulating PPARGC1A and NFE2L2-ARE pathways in cell models of spinocerebellar ataxia 3. Free Radic Biol Med 2014;71:339-50. doi: 10.1016/j.freeradbiomed.2014.03.023
    連結:
  17. Velazquez-Perez L, Rodriguez-Chanfrau J, Garcia-Rodriguez JC, et al. Oral zinc sulphate supplementation for six months in SCA2 patients: a randomized, double-blind, placebo-controlled trial. Neurochem Res 2011;36:1793-800. doi: 10.1007/s11064-011-0496-0
    連結:
  18. Jimenez-Sanchez M, Thomson F, Zavodszky E, et al. Autophagy and polyglutamine diseases. Prog Neurobiol 2012;97:67-82. doi: 10.1016/j.pneurobio.2011.08.013
    連結:
  19. Chen IC, Chang KH, Chen YJ, et al. Pueraria iobata and daidzein reduce cytotoxicity by enhancing ubiquitin-proteasome system function in SCA3-iPSC-derived neurons. Oxid Med Cell Longev 2019;2019:8130481. doi: 10.1155/2019/8130481
    連結:
  20. Ashkenazi A, Bento CF, Ricketts T, et al. Polyglutamine tracts regulate beclin 1-dependent autophagy. Nature 2017;545:108-11. doi: 10.1038/nature22078
    連結:
  21. Liang XH, Jackson S, Seaman M, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999;402:672-6. doi: 10.1038/45257
    連結:
  22. Sittler A, Muriel MP, Marinello M, et al. Deregulation of autophagy in postmortem brains of Machado-Joseph disease patients. Neuropathology 2018;38:113-24. doi: 10.1111/neup.12433
    連結:
  23. Chen ZZ, Wang CM, Lee GC, et al. Trehalose attenuates the gait ataxia and gliosis of spinocerebellar ataxia type 17 mice. Neurochem Res 2015;40:800-10. doi: 10.1007/s11064-015-1530-4
    連結:
  24. Lee GC, Lin CH, Tao YC, et al. The potential of lactulose and melibiose, two novel trehalase-indigestible and autophagy-inducing disaccharides, for polyQ-mediated neurodegenerative disease treatment. Neurotoxicology 2015;48:120-30. doi: 10.1016/j.neuro.2015.03.009
    連結:
  25. Saibil H. Chaperone machines for protein folding, unfolding and disaggregation. Nat Rev Mol Cell Biol 2013;14:630-42. doi: 10.1038/nrm3658
    連結:
  26. Lee LC, Chen CM, Chen FL, et al. Altered expression of HSPA5, HSPA8 and PARK7 in spinocerebellar ataxia type 17 identified by 2-dimensional fluorescence difference in gel electrophoresis. Clin Chim Acta 2009;400:56-62. doi: 10.1016/j.cca.2008.10.013
    連結:
  27. Chang KH, Chen WL, Lee LC, et al. Aqueous extract of Paeonia lactiflora and paeoniflorin as aggregation reducers targeting chaperones in cell models of spinocerebellar ataxia 3. Evid Based Complement Alternat Med 2013;2013:471659. doi: 10.1155/2013/471659
    連結:
  28. Kung PJ, Tao YC, Hsu HC, et al. Indole and synthetic derivative activate chaperone expression to reduce polyQ aggregation in SCA17 neuronal cell and slice culture models. Drug Des Devel Ther 2014;8:1929-39. doi: 10.2147/DDDT.S67376
    連結:
  29. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996;87:543-52. doi: 10.1016/S0092-8674(00)81373-2
    連結:
  30. Chen X, Tang TS, Tu H et al. Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3. J Neurosci 2008;28:12713-24. doi: 10.1523/JNEUROSCI.3909-08.2008
    連結:
  31. Hansen ST, Meera P, Otis TS et al. Changes in Purkinje cell firing and gene expression precede behavioral pathology in a mouse model of SCA2. Hum Mol Genet 2013;22:271-83. doi: 10.1093/hmg/dds427
    連結:
  32. Huang S, Ling JJ, Yang S, et al. Neuronal expression of TATA box-binding protein containing expanded polyglutamine in knock-in mice reduces chaperone protein response by impairing the function of nuclear factor-Y transcription factor. Brain 2011;134:1943-58. doi: 10.1093/brain/awr146
    連結:
  33. Lin X, Antalffy B, Kang D, et al. Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat Neurosci 2000;3:157-63. doi: 10.1038/72101
    連結:
  34. Romano S, Coarelli G, Marcotulli C, et al. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2015;14:985-91. doi: 10.1016/S1474-4422(15)00201-X
    連結:
  35. Zesiewicz TA, Greenstein PE, Sullivan KL, et al. A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3. Neurology 2012;78:545-50. doi: 10.1212/WNL.0b013e318247cc7a
    連結:
  36. Liu CS, Hsu HM, Cheng WL, et al. Clinical and molecular events in patients with Machado-Joseph disease under lamotrigine therapy. Acta Neurol Scand 2005;111:385-90. doi: 10.1111/j.1600-0404.2005.00405.x
    連結:
  37. Yabe I, Sasaki H, Yamashita I, et al. Clinical trial of acetazolamide in SCA6, with assessment using the Ataxia Rating Scale and body stabilometry. Acta Neurol Scand 2001;104:44-7. doi: 10.1034/j.1600-0404.2001.00299.x
    連結:
  38. Chiu YJ, Lin SA, Chen WL, et al. Pathomechanism characterization and potential therapeutics identification for SCA3 targeting neuroinflammation. Aging 2020;12:23619-46. doi: 10.18632/aging.103700
    連結:
  39. Rekatsina M, Paladini A, Piroli A, et al. Pathophysiology and therapeutic perspectives of oxidative stress and neurodegenerative diseases: a narrative review. Adv Ther 2020;37:113-39. doi: 10.1007/s12325-019-01148-5
    連結:
  40. Evert BO, Vogt IR, Kindermann C, et al. Inflammatory genes are upregulated in expanded ataxin-3-expressing cell lines and spinocerebellar ataxia type 3 brains. J Neurosci 2001;21:5389-96. doi: 10.1523/JNEUROSCI.21-15-05389.2001
    連結:
  41. Tsai YA, Liu RS, Lirng JF, et al. Treatment of spinocerebellar ataxia with mesenchymal stem cells: a phase I/IIa clinical study. Cell Transplant 2017;26:503-12. doi: 10.3727/096368916X694373
    連結:
  42. Niewiadomska-Cimicka A, Hache A, Trottier Y. Gene dregulation and underlying mechanisms in spinocerebellar ataxias with polyglutamine expansion. Front Neurosci 2020;14:571. doi: 10.3389/fnins.2020.00571
    連結:
  43. Liu Q, Pan Y, Li XJ, et al. Molecular mechanisms and therapeutics for SCA17. Neurotherapeutics 2019;16:1097-105. doi: 10.1007/s13311-019-00762-z
    連結:
  44. Palhan VB, Chen S, Peng GH, et al. Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration. Proc Natl Acad Sci U S A 2005;102:8472-7. doi: 10.1073/pnas.0503505102
    連結:
  45. Lei LF, Yang GP, Wang JL, et al. Safety and efficacy of valproic acid treatment in SCA3/MJD patients. Parkinsonism Relat Disord 2016;26:55-61. doi: 10.1016/j.parkreldis.2016.03.005
    連結:
  46. Mykowska A, Sobczak K, Wojciechowska M, et al. CAG repeats mimic CUG repeats in the misregulation of alternative splicing. Nucleic Acids Res 2011;39:8938-51. doi: 10.1093/nar/gkr608
    連結:
  47. Scoles DR, Ho MH, Dansithong W, et al. Repeat associated non-AUG translation (RAN translation) dependent on sequence downstream of the ATXN2 CAG repeat. PLoS One 2015;10:e0128769. doi: 10.1371/journal.pone.0128769
    連結:
  48. Marti E. RNA toxicity induced by expanded CAG repeats in Huntington's disease. Brain Pathol 2016;26:779-86. doi: 10.1111/bpa.12427
    連結:
  49. de Mezer M, Wojciechowska M, Napierala M, et al. Mutant CAG repeats of Huntingtin transcript fold into hairpins, form nuclear foci and are targets for RNA interference. Nucleic Acids Res 2011;39:3852-63. doi: 10.1093/nar/gkq1323
    連結:
  50. Jasinska A, Michlewski G, de Mezer M, et al. Structures of trinucleotide repeats in human transcripts and their functional implications. Nucleic Acids Res 2003;31:5463-8. doi: 10.1093/nar/gkg767
    連結:
  51. Zhang MM, Bahal R, Rasmussen TP, et al. The growth of siRNA-based therapeutics: updated clinical studies. Biochem Pharmacol 2021;189:114432. doi: 10.1016/j.bcp.2021.114432
    連結:
  52. Alves S, Nascimento-Ferreira I, Auregan G, et al. Allele-specific RNA silencing of mutant ataxin-3 mediates neuroprotection in a rat model of Machado-Joseph disease. PLoS One 2008;3:e3341. doi: 10.1371/journal.pone.0003341
    連結:
  53. Conceicao M, Mendonca L, Nobrega C, et al. Intravenous administration of brain-targeted stable nucleic acid lipid particles alleviates Machado-Joseph disease neurological phenotype. Biomaterials 2016;82:124-37. doi: 10.1016/j.biomaterials.2015.12.021
    連結:
  54. Xia H, Mao Q, Eliason SL, et al. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med 2004;10:816-20. doi: 10.1038/nm1076
    連結:
  55. McIntosh CS, Li D, Wilton SD, et al. Polyglutamine ataxias: our current molecular understanding and what the future holds for antisense therapies. Biomedicines 2021;9:1499. doi: 10.3390/biomedicines9111499
    連結:
  56. Friedrich J, Kordasiewicz HB, O'Callaghan B, et al. Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles. JCI Insight 2018;3:e123193. doi: 10.1172/jci.insight.123193
    連結:
  57. Niu C, Prakash TP, Kim A, et al. Antisense oligonucleotides targeting mutant Ataxin-7 restore visual function in a mouse model of spinocerebellar ataxia type 7. Sci Transl Med 2018;10:eaap8677. doi: 10.1126/scitranslmed.aap8677
    連結:
  58. Scoles DR, Meera P, Schneider MD, et al. Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Nature 2017;544:362-6. doi: 10.1038/nature22044
    連結:
  59. Toonen LJA, Rigo F, van Attikum H, et al. Antisense oligonucleotide-mediated removal of the polyglutamine repeat in spinocerebellar ataxia type 3 mice. Mol Ther Nucleic Acids 2017;8:232-42. doi: 10.1016/j.omtn.2017.06.019
    連結:
  60. Kwon D. Failure of genetic therapies for Huntington's devastates community. Nature 2021;593:180. doi: 10.1038/d41586-021-01177-7
    連結:
  61. 陳聰富:醫療責任的形成與展開,修訂版。臺北:國立臺灣大學出版中心,2019:2-4。 doi: 10.978.986350/3729
    連結:
  62. 張宇葭:美容醫學醫療糾紛之民事法律關係。月旦醫事法報告2022;64:22-31。 doi: 10.53106/241553062022020064002
    連結:
  63. 劉傳璟:單純美容醫療行為之刑法評價。月旦醫事法報告2022;64:7-21。 doi: 10.53106/241553062022020064001
    連結:
  64. 陳聰富:醫療責任的形成與展開,修訂版。臺北:國立臺灣大學出版中心,2019:27。 doi: 10.978.986350/3729
    連結:
  65. 黃鈺媖:美容醫學廣告管制與法律效力。月旦醫事法報告2022;64:46-57。 doi: 10.53106/241553062022020064004
    連結:
  66. 廖建瑜:從判決快遞看醫療訴訟的發展趨勢。月旦醫事法報告2019;36:113-40。
  67. 廖建瑜:從地方法院民事醫療判決看最新發展趨勢-引用最高法院次數觀察。月旦醫事法報告2021;56:7-29。
  68. 朱柏松:整型、美容醫學之區別及其廣告應有之法規範。月旦法學教室2005;31:92-104。
  69. 吳志正:解讀醫病關係I:醫療契約篇。臺北:元照,2006:34-5。
  70. 衛生福利部醫事司:衛生署推動美容醫學機構認證及執業人員之相關管理。https://www.mohw.gov.tw/cp-2640-23721-1.html/ Accessed February 28, 2022.
  71. 魏伶娟:論非治療性微整型美容與消費者保護法之適用。高大法學論叢2017;12:245-98。
  72. 最高法院103年度台上字第4387號、109年度台上字第2925號刑事判決。
  73. 王澤鑑:侵權行為法,增訂新版。臺北:自版,2015:5。
  74. 最高法院90年台上字第709號、臺灣高等法院87年度上字第151號、88年度重上字第505號、91年度上字第597號、92年度上字第596號民事判決。
  75. 最高法院95年台上字第2178號、96年台上字第450號、96年台上字第2738號、97年台上字第741號民事判決。
  76. 劉宏恩:醫美亂象與消費者保護法的適用。消費者報導雜誌2014;400:56-61。
  77. 衛生福利部醫事司:衛生福利部關於消基會發表「非必要性之美容行為應屬消費行為,應受消保法規範」回應說明。https://www.mohw.gov.tw/cp-3201-21989-1.html/ Accessed February 28, 2022.
  78. 史尚寬:債法各論(上)。臺北:自版,1986:361。
  79. 黃丁全:醫事法。臺北:元照,2000:246。
  80. 林誠二:民法債編各論(中)。臺北:瑞興,2002:71-2。
  81. 邱聰智:新訂債法各論(中)。臺北:自版,2002:192。
  82. 劉春堂:民法債編各論(中)。臺北:三民,2007:136-7。
  83. 陳聰富:醫療契約之法律關係(上)。月旦法學教室2008;72:89-98。
  84. 最高法院53年度台上字第2354號、70年度台上字第1049號、82年度台上字第267號、92年度台上字第1057號、93年度重上字第60號民事判決。
  85. Wolfgang Neuefeind: Arzthaftungsrecht, 2. Aufl. Marburg, Tectum, 1997: S. 31 f.
  86. 最高法院103年度台上字第560號民事判決。