RNA靶向和基因编辑药物在转甲状腺素蛋白淀粉样变心肌病中的研究进展

牛子冉; 胡扬; 刘清扬; 马元元; 刘佳宁; 刘鑫; 张波

doi:10.12376/j.issn.2097-0501.2023.01.013

RNA靶向和基因编辑药物在转甲状腺素蛋白淀粉样变心肌病中的研究进展

doi: 10.12376/j.issn.2097-0501.2023.01.013

中国医学科学院北京协和医院药剂科，北京 100730

基金项目:

中央高水平医院临床科研业务费 2022-PUMCH-B-059

详细信息

通信作者:
张波，E-mail: zhangbopumch@163.com

中图分类号: R542.2
计量
- 文章访问数: 10
- HTML全文浏览量: 6
- PDF下载量: 2
- 被引次数: 0
出版历程
- 收稿日期: 2022-12-06
- 录用日期: 2022-12-20
- 网络出版日期: 2023-03-07

Progress in RNA-targeting and Gene Editing Therapies for Transthyretin Amyloidosis Cardiomyopathy

Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

Funding:

National High Level Hospital Clinical Research Funding 2022-PUMCH-B-059

More Information

Corresponding author: ZHANG Bo, E-mail: zhangbopumch@163.com

摘要

摘要: 转甲状腺素蛋白(TTR)是一种主要由肝脏合成的四聚体蛋白，可错误折叠并沉积为淀粉样原纤维，沉积于心肌间质导致转甲状腺素蛋白淀粉样变心肌病(ATTR-CM)。ATTR-CM列入中国《第一批罕见病目录》，治疗策略包括阻断肝脏中TTR合成、稳定TTR四聚体和破坏TTR原纤维。氯苯唑酸、二氟尼柳等小分子药物为患者提供新的治疗选择。其中氯苯唑酸成为首个美国食品药品监督管理局(FDA)批准用于治疗ATTR-CM的药物。小干扰RNA(siRNA)patisiran和反义寡核苷酸(ASO)inotersen阻断肝脏TTR表达，并已批准用于治疗变异ATTR多发性神经病(ATTRv-PN)，用于治疗ATTR-CM正在进行Ⅲ期试验，其他siRNA药物vutrisiran和ASO制剂eplontersen临床效果正在评估中。本文介绍RNA靶向治疗药物及使用CRISPR-Cas9进行基因编辑药物的研究进展。
- 转甲状腺素蛋白淀粉样变心肌病 /
- 小干扰RNA /
- 反义寡核苷酸 /
- 基因编辑
Abstract: Transthyretin(TTR) protein is a tetramer protein, synthesized mainly by the liver. TTR can be misfolded and deposited as amyloid fibrilae and deposited in the myocardial interstroma leading to transthyroxin amyloidosis cardiomyopathy (ATTR-CM). ATTR-CM was included in China's First List of Rare Diseases. Therapeutic strategies for ATTR-CM include blocking TTR synthesis in the liver, stabilizing TTR tetramers and destroying TTR fibra. Small molecule drugs such as tafamidis and diflunisal offer new treatment options for patients. Chlorobenzolic acid became the first drug approved by the U.S. Food and Drug Administration for the treatment of ATTR-CM. Small interfering RNA(siRNA)patisiran and antisense oligonucleotide (ASO)inotersen block TTR expression in the liver and have been approved for the treatment of ATTR variant polyneuropathy (ATTRv-PN)and are in phase Ⅲ trials for the treatment of ATTR-CM. Other siRNA drugs, vutrisiran, and ASO, eplontersen, are being evaluated for clinical efficacy. This article reviews the development of RNA-targeted therapeutics and gene-editing drugs using CRISPR-Cas9.
- ransthyretin amyloidosis caridomyopathy /
- siRNA /
- antisense oligonucleotide /
- gene-editing
注释:

作者贡献：牛子冉和张波参与选题、文献检索，以及论文构思和撰写；胡扬、刘清扬、马元元、刘佳宁、刘鑫参与文献检索及论文构思。

利益冲突：所有作者均声明不存在利益冲突。

HTML全文

参考文献(50)

[1]	Benson MD, Buxbaum JN, Eisenberg DS, et al. Amyloid nomenclature 2020: update and recommendations by the International Society of Amyloidosis (ISA) nomenclature committee[J]. Amyloid, 2020, 27(4): 217-222. doi: 10.1080/13506129.2020.1835263
[2]	Ruberg FL, Grogan M, Hanna M, et al. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review[J]. J Am Coll Cardiol, 2019, 73(22): 2872-2891. doi: 10.1016/j.jacc.2019.04.003
[3]	Vieira M, Saraiva MJ. Transthyretin: a multifaceted protein[J]. Biomol, 2014, 5(1): 45-54.
[4]	Kelly JW, Colon W, Lai Z, et al. Transthyretin quater-nary and tertiary structural changes facilitate misassembly into amyloid[J]. Adv Protein Chem, 1997, 50: 161-181. doi: 10.1016/S0065-3233(08)60321-6
[5]	Griffin JM, Rosenblum H, Maurer MS, et al. Pathophysiology and therapeutic approaches to cardiac amyloidosis[J]. CircRes, 2021, 128(10): 1554-1575.
[6]	Maurer MS, Bokhari S, Damy T, et al. Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis[J]. Circ Heart Fail, 2019, 12(9): e006075. doi: 10.1161/CIRCHEARTFAILURE.119.006075
[7]	Adams D, Koike H, Slama M, et al. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease[J]. Nat Rev, 2019, 15(7): 387-404.
[8]	Li B, Alvir J, Stewart M. Extrapolation of survival benefits in patients with transthyretin amyloid cardiomyopathy receiving tafamidis: analysis of the tafamidis in transthyretin cardio-myopathy clinical trial[J]. Cardiol, 2020, 9(2): 535-540.
[9]	Ericzon BG, Wilczek HE, Larsson M, et al. Liver transplantation for hereditary transthyretin amyloidosis: after 20 years still the best therapeutic alternative?[J]. Transplantation, 2015, 99(9): 1847-1854. doi: 10.1097/TP.0000000000000574
[10]	Okamoto S, Zhao Y, Lindqvist P, et al. Development of cardiomyopathy after liver transplantation in Swedish hereditary transthyretin amyloidosis(ATTR) patients[J]. Amyloid, 2011, 18(4): 200-205. doi: 10.3109/13506129.2011.615872
[11]	Emdin M, Aimo A, Rapezzi C, et al. Treatment of cardiac transthyretin amyloidosis: an update[J]. Eur Heart J, 2019, 40(45): 3699-3706. doi: 10.1093/eurheartj/ehz298
[12]	田庄, 张抒扬. 氯苯唑酸治疗转甲状腺素心脏淀粉样变[J]. 中华心血管病杂志, 2021, 49(4): 314-317. doi: 10.3760/cma.j.cn112148-20200920-00748
[13]	Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy[J]. N Engl J Med, 2018, 379(11): 1007-1016. doi: 10.1056/NEJMoa1805689
[14]	Seferovic PM, Ponikowski P, Anker SD, et al. Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology[J]. Eur J Heart Fail, 2019, 21(10): 1169-1186. doi: 10.1002/ejhf.1531
[15]	Solomon SD, Adams D, Kristen A, et al. Effects of patisiran, an rna interference therapeutic, on cardiac parameters in patients with hereditary transthyretin-mediated amyloidosis[J]. Circulation, 2019, 139(4): 431-443. doi: 10.1161/CIRCULATIONAHA.118.035831
[16]	Hu B, Zhong L, Weng Y, et al. Therapeutic siRNA: state of the art[J]. Signal Transduct Target Ther, 2020, 5(1): 101. doi: 10.1038/s41392-020-0207-x
[17]	Setten RL, Rossi JJ, Han SP. The current state and future directions of RNAi-based therapeutics[J]. Nat Rev Drug Discov, 2019, 18(6): 421-446. doi: 10.1038/s41573-019-0017-4
[18]	Pasi KJ, Rangarajan S, Georgiev P, et al. Targeting of antithrombin in hemophilia A or B with RNAi therapy[J]. N Engl J Med, 2017, 377(9): 819-828. doi: 10.1056/NEJMoa1616569
[19]	Kamerkar S, LeBleu VS, Sugimoto H, et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancre-atic cancer[J]. Nature, 2017, 546(7659): 498-503. doi: 10.1038/nature22341
[20]	Pham TP, Kremer V, Boon RA. RNA-based therapeutics in cardiovascular disease[J]. Curr Opin Cardiol, 2020, 35(3): 191-198. doi: 10.1097/HCO.0000000000000724
[21]	Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis[J]. N Engl J Med, 2013, 369(9): 819-829. doi: 10.1056/NEJMoa1208760
[22]	U.S. Food and Drug Administration. Onpattro (patisiran) labeling-package insert. FDA[J/OL ]. (2022-04-13)[2022-12-01]. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=210922.
[23]	Suhr OB, Coelho T, Buades J, et al. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase Ⅱ multi-dose study[J]. Orphanet J Rare Dis, 2015, 10: 109. doi: 10.1186/s13023-015-0326-6
[24]	Coelho T, Adams D, Conceição I, et al. A phase Ⅱ, open-label, extension study of long-term patisiran treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis[J]. Orphanet J Rare Dis, 2020, 15(1): 179. doi: 10.1186/s13023-020-01399-4
[25]	Adams D, Gonzalez-Duarte A, O'Riordan WD, et al. Patisiran, an RNA therapeutic for hereditary transthyretin amyloidosis[J]. N Engl J Med, 2018, 379(1): 11-21. doi: 10.1056/NEJMoa1716153
[26]	Fontana M, Martinez-Naharro A, Chacko L, et al. Reduction in CMR derived extracellular volume with patisiran indicates cardiac amyloid regression[J]. JACC Cardiovasc Imaging, 2021, 14(1): 189-199. doi: 10.1016/j.jcmg.2020.07.043
[27]	US National Library of Medicine: ClinicalTrials. gov[J/OL ]. (2022-08-13)[2022-12-01]. http://www.clinicaltrials.gov/ct2/show/NCT03997383.
[28]	Adams D, Polydefkis M, González-Duarte A, et al. Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study[J]. Lancet Neurol, 2021, 20(1): 49-59. doi: 10.1016/S1474-4422(20)30368-9
[29]	European Medicines Agency: Onpattro. EMA[J/OL]. (2022-05-12)[2022-12-01]. https://www.ema.europa.eu/en/medicines/human/EPAR/onpattro.
[30]	Habtemariam BA, Karsten V, Attarwala H, et al. Single-dose pharmacokinetics and pharmacodynamics of trans-thyretin targeting n-acetylgalactosamine-small interfering ribonucleic acid conjugate, vutrisiran, in healthy subjects[J]. Clin Pharmacol Ther, 2021, 109(2): 372-382. doi: 10.1002/cpt.1974
[31]	US National Library of Medicine: ClinicalTrials. gov[J/OL]. (2022-03-16)[2022-12-01]. http://www.clinical-trials.gov/ct2/show/NCT03759379.
[32]	US National Library of Medicine: ClinicalTrials. gov[J/OL]. (2022-08-23)[2022-12-01]. http://www.clinicaltrials.gov/ct2/show/NCT04153149.
[33]	Judge DP, Kristen AV, Grogan M, et al. Phase 3 multicenter study of revusiran in patients with hereditary transthyretin-mediated (hattr) amyloidosis with cardiomyopathy (endeavour)[J]. Cardiovasc Drugs Ther, 2020, 34(3): 357-370. doi: 10.1007/s10557-019-06919-4
[34]	Viney NJ, Guo S, Tai LJ, et al. Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data[J]. ESC Heart Fail, 2021, 8(1): 652-661. doi: 10.1002/ehf2.13154
[35]	US Food and Drug Administration: Tegsedi (inotersen) labeling-medication guide. FDA[J/OL]. (2020-12-15)[2022-09-11]. https//www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=211172.
[36]	Ackermann EJ, Guo SL, Benson MD. Suppressing transthyretin production in mice, monkeys and humans using 2nd-generation antisense oligonucleotides[J]. Amyloid, 2016, 23(3): 148-157. doi: 10.1080/13506129.2016.1191458
[37]	US National Library of Medicine. ClinicalTrials.gov[EB/OL].(2020-12-07)[2022-08-11].http://www.clinicaltrials.gov/ct2/show/NCT03702829.
[38]	Benson MD, Márcia WC, Berk JL, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis[J]. N Engl J Med, 2018, 379(1): 22-31. doi: 10.1056/NEJMoa1716793
[39]	Luigetti M, Antonini G, Di Paolantonio A, et al. Real-life experience with inotersen in hereditary transthyretin amyloidosis with late-onset phenotype: data from an early-access program in Italy[J]. Eur J Neurol, 2022, 29(7): 2148-2155. doi: 10.1111/ene.15325
[40]	European Medicines Agency. Tegsedi. EMA[EB/OL].(2022-03-18)[2022-08-11].https://www.ema.europa.eu/en/medicines/human/EPAR/tegsedi#authorisation-de-tails-section.
[41]	Viney NJ, Guo SL, Tai LJ, et al. Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data[J]. ESC Heart Fail, 2021, 8(1), 652-661. doi: 10.1002/ehf2.13154
[42]	US National Library of Medicine. ClinicalTrials.gov[EB/OL].(2021-04-15)[2022-12-01].http://www.clinicaltrials.gov/ct2/show/NCT04843020.
[43]	US National Library of Medicine. ClinicalTrials.gov [EB/OL].(2022-09-30)[2022-12-01].http://www.clini-caltrials.gov/ct2/show/NCT04136184.
[44]	Li H, Yang Y, Hong W, et al. Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects[J]. Signal Transduct Target Ther, 2020, 5(1): 1. doi: 10.1038/s41392-019-0089-y
[45]	Gillmore JD, Gane E, Taubel J, et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis[J]. N Engl J Med, 2021, 385(6): 493-502. doi: 10.1056/NEJMoa2107454
[46]	Maurer MS. Gene editing-a cure for transthyretin amyloi-dosis?[J]. N Engl J Med, 2021, 385(6): 558-559. doi: 10.1056/NEJMe2110557
[47]	Finn JD, Smith AR, Patel MC, et al. A single administration of crispr/cas9 lipid nanoparticles achieves robust and persistent in vivo genome editing[J]. Cell Rep, 2018, 22(9): 2227-2235. doi: 10.1016/j.celrep.2018.02.014
[48]	Rapezzi C, Aim A, Pavasini R. Longitudinal strain in the management of cardiac AL amyloidosis: do we need it?[J]. Eur Heart J, 2022, 43(4): 342-344. doi: 10.1093/eurheartj/ehab609
[49]	Kazi DS, Bellows BK, Baron SJ, et al. Cost-effectiveness of tafamidis therapy for transthyretin amyloid cardiomyopathy[J]. Circulation, 2020, 141(15): 1214-1224. doi: 10.1161/CIRCULATIONAHA.119.045093
[50]	Aimo A, Castiglione V, Rapezzi C, et al. RNA-targeting and gene editing therapies for transthyretin amyloidosis[J]. Nat Rev Cardiol, 2022, 19: 655-667. doi: 10.1038/s41569-022-00683-z