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靶向亨廷顿病患者的亨廷顿蛋白表达
Targeting Huntingtin Expression in Patients with Huntington’s Disease


Sarah J. Tabrizi ... 其他 • 2019.06.13

首个针对亨廷顿舞蹈病病因的临床试验,燃起新希望

 

鲁伯埙†*,党永军‡

†复旦大学生命科学学院;‡复旦大学基础医学院

*通讯作者

 

亨廷顿病(HD)是一种神经退行性疾病,因其患者步伐不稳和非自主的运动,又称为亨廷顿舞蹈病。亨廷顿病病程缓慢,随时间逐步恶化,目前尚无有效治疗手段,其患者最终死于肺炎、心力衰竭或其他并发症。

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摘要


背景

亨廷顿病是一种常染色体显性遗传的神经退行性疾病,病因是产生突变型亨廷顿蛋白的HTT CAG三核苷酸重复扩增。IONIS-HTTRx(下文简称HTTRx)是一种反义寡核苷酸,旨在抑制HTT信使RNA,从而降低突变型亨廷顿蛋白浓度。

 

方法

我们开展了一项纳入早期亨廷顿病成人患者的随机、双盲、多种递增剂量1~2a期试验。本试验以3∶1的比例将患者随机分组,分别接受每4周1次HTTRx或安慰剂鞘内泵给药,共给药4次。剂量选择是由小鼠和非人灵长类动物的临床前模型指导,该模型在剂量水平与亨廷顿蛋白浓度降低之间建立了关联。主要终点是安全性。次要终点是脑脊液(CSF)中的HTTRx药代动力学。预设的探索性终点包括CSF中的突变型亨廷顿蛋白浓度。

 

结果

在纳入试验的46例患者中,34例被随机分配接受HTTRx(10~120 mg递增剂量),12例被随机分配接受安慰剂。每例患者均接受了全部4次给药,并完成了试验。98%的患者报告了不良事件,不良事件全部为1或2级。在接受HTTRx治疗的患者中未观察到严重不良事件。实验室变量未发生有临床意义的不良变化。截至60 mg剂量,CSF中HTTRx的给药前(谷)浓度显示出剂量依赖性。HTTRx治疗使CSF中的突变型亨廷顿蛋白浓度出现剂量依赖性降低(相对于基线的平均变化百分比,安慰剂组为10%,HTTRx 10 mg、30 mg、60 mg、90 mg和120 mg剂量组分别为-20%、-25%、-28%、-42%和-38%)。

 

结论

早期亨廷顿病患者接受HTTRx鞘内给药未伴发严重不良事件。我们观察到突变型亨廷顿蛋白浓度出现剂量依赖性降低(由伊奥尼斯制药公司[Ionis Pharmaceuticals]和罗氏制药公司资助;在ClinicalTrials.org注册号为NCT02519036)。





作者信息

Sarah J. Tabrizi, M.B., Ch.B., Ph.D., Blair R. Leavitt, M.D., C.M., G. Bernhard Landwehrmeyer, M.D., Edward J. Wild, M.B., B.Chir., Ph.D., Carsten Saft, M.D., Roger A. Barker, M.R.C.P., Ph.D., Nick F. Blair, M.B., B.S., David Craufurd, M.B., B.S., Josef Priller, M.D., Hugh Rickards, M.D., Anne Rosser, M.B., B.Chir., Ph.D., Holly B. Kordasiewicz, Ph.D., Christian Czech, Ph.D., Eric E. Swayze, Ph.D., Daniel A. Norris, Ph.D., Tiffany Baumann, B.S., Irene Gerlach, Ph.D., Scott A. Schobel, M.D., Erika Paz, B.S., Anne V. Smith, Ph.D., C. Frank Bennett, Ph.D., and Roger M. Lane, M.D.
From University College London (UCL) Huntington’s Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke’s Hospital, University of Cambridge, Cambridge (R.A.B., N.F.B.), Manchester Centre for Genomic Medicine, St. Mary’s Hospital, Manchester University NHS Foundation Trust, and the Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester (D.C.), the University of Edinburgh and the U.K. Dementia Research Institute, Edinburgh (J.P.), the Institute of Clinical Sciences, College of Medical and Dental Sciences, University Hospital Birmingham, Birmingham (H.R.), and the Cardiff University Brain Repair Group, Brain Repair and Intracranial Neurotherapeutics Unit, Neuroscience and Mental Health Research Institute and School of Biosciences, Cardiff (A.R.) — all in the United Kingdom; the Centre for Huntington’s Disease, Department of Medical Genetics, and the Division of Neurology, Department of Medicine, University of British Columbia, and the Centre for Molecular Medicine and Therapeutics, B.C. Children’s Hospital, Vancouver, Canada (B.R.L.); the Department of Neurology, Ulm University, Huntington’s Disease Centre, Ulm (G.B.L.), the Department of Neurology, Huntington Center North Rhine–Westphalia, Ruhr University Bochum, St. Josef–Hospital, Bochum (C.S.), and the Department of Neuropsychiatry, Charité–Universitätsmedizin Berlin, Deutsches Zentrum für Neurodegenerative Erkrankungen, Berlin (J.P.) — all in Germany; Ionis Pharmaceuticals, Carlsbad, CA (H.B.K., E.E.S., D.A.N., T.B., E.P., A.V.S., C.F.B., R.M.L.); and F. Hoffmann–La Roche, Basel, Switzerland (C.C., I.G., S.A.S.). Address reprint requests to Dr. Tabrizi at University College London, Huntington’s Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, London WC1N 3BG, United Kingdom, or at s.tabrizi@ucl.ac.uk. Nick F. Blair, M.B., B.S., is deceased.

 

参考文献

1. Bates GP, Dorsey R, Gusella JF, et al. Huntington disease. Nat Rev Dis Primers 2015;1:15005-15005.

2. The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 1993;72:971-983.

3. Andrew SE, Goldberg YP, Kremer B, et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington’s disease. Nat Genet 1993;4:398-403.

4. Ross CA, Tabrizi SJ. Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 2011;10:83-98.

5. Lane RM, Smith A, Baumann T, et al. Translating antisense technology into a treatment for Huntington’s disease. Methods Mol Biol 2018;1780:497-523.

6. Bennett CF, Swayze EE. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol 2010;50:259-293.

7. Kordasiewicz HB, Stanek LM, Wancewicz EV, et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron 2012;74:1031-1044.

8. Keiser MS, Kordasiewicz HB, McBride JL. Gene suppression strategies for dominantly inherited neurodegenerative diseases: lessons from Huntington’s disease and spinocerebellar ataxia. Hum Mol Genet 2016;25:R1:R53-R64.

9. Wild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in Huntington’s disease. Lancet Neurol 2017;16:837-847.

10. Harper SQ, Staber PD, He X, et al. RNA interference improves motor and neuropathological abnormalities in a Huntington’s disease mouse model. Proc Natl Acad Sci U S A 2005;102:5820-5825.

11. Huntington Study Group. Unified Huntington’s Disease Rating Scale: reliability and consistency. Mov Disord 1996;11:136-142.

12. Freeborough PA, Fox NC. The boundary shift integral: an accurate and robust measure of cerebral volume changes from registered repeat MRI. IEEE Trans Med Imaging 1997;16:623-629.

13. Penney JB Jr, Vonsattel JP, MacDonald ME, Gusella JF, Myers RH. CAG repeat number governs the development rate of pathology in Huntington’s disease. Ann Neurol 1997;41:689-692.

14. Schobel SA, Palermo G, Auinger P, et al. Motor, cognitive, and functional declines contribute to a single progressive factor in early HD. Neurology 2017;89:2495-2502.

15. Southwell AL, Smith SE, Davis TR, et al. Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression. Sci Rep 2015;5:12166-12166.

16. Tabrizi SJ, Langbehn DR, Leavitt BR, et al. Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol 2009;8:791-801.

17. Crotti A, Glass CK. The choreography of neuroinflammation in Huntington’s disease. Trends Immunol 2015;36:364-373.

18. Ellrichmann G, Reick C, Saft C, Linker RA. The role of the immune system in Huntington’s disease. Clin Dev Immunol 2013;2013:541259-541259.

19. Zivadinov R, Reder AT, Filippi M, et al. Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis. Neurology 2008;71:136-144.

20. De Stefano N, Arnold DL. Towards a better understanding of pseudoatrophy in the brain of multiple sclerosis patients. Mult Scler 2015;21:675-676.

21. Novak G, Fox N, Clegg S, et al. Changes in brain volume with bapineuzumab in mild to moderate Alzheimer’s disease. J Alzheimers Dis 2016;49:1123-1134.

22. Fox NC, Black RS, Gilman S, et al. Effects of Aβ immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology 2005;64:1563-1572.

23. Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014;370:322-333.

24. Nave S, Doody RS, Boada M, et al. Sembragiline in moderate Alzheimer’s disease: results of a randomized, double-blind, placebo-controlled Phase II trial (MAyflOwer RoAD). J Alzheimers Dis 2017;58:1217-1228.

25. Khalil M, Teunissen CE, Otto M, et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol 2018;14:577-589.

26. Byrne LM, Rodrigues FB, Johnson EB, et al. Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington’s disease. Sci Transl Med 2018;10:10-10.

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