血友病基因治疗临床研究进展

张磊; 代新岳

doi:10.13201/j.issn.1004-2806.2022.07.003

血友病基因治疗临床研究进展

张磊^1, ,,
代新岳¹

- 中国医学科学院血液病医院(中国医学科学院血液学研究所)，实验血液学国家重点实验室，国家血液系统疾病临床医学研究中心(天津，300020)

详细信息

作者简介:
张磊，医学博士、主任医师、博士生导师。担任中国医学科学院血液病医院血液学研究所副所院长，国家血液系统疾病临床医学研究中心副主任，实验血液学国家重点实验室副主任，中国医学科学院基因治疗重点实验室主任，天津市血液病基因治疗重点实验室主任，天津市血液与再生医学理事长，Global Medical Genetics主编，《中华血液学杂志》编委，“协和学者”特聘教授，“津门医学英才”。从事出凝血疾病和血小板疾病的诊断与治疗。承担国家及省部级科研项目课题15项，国际合作基金2项。在Cell Stem Cell、Blood以及Leukemia等国内外知名专业期刊发表SCI论文百余篇，申请专利4项。获国家级奖1项，获省部级奖4项

通讯作者: 张磊，E-mail：zhanglei1@ihcams.ac.cn

中图分类号: R554.1

收稿日期: 2022-05-25

刊出日期: 2022-07-01

Clinical research progress of gene therapy for hemophilia

ZHANG Lei^1, ,,
DAI Xinyue¹

More Information

Corresponding author: ZHANG Lei, E-mail: zhanglei1@ihcams.ac.cn

Received Date: 25 May 2022

Publish Date: 01 July 2022

摘要

- 血友病 /
- 基因治疗 /
- 腺相关病毒载体
- hemophilia /
- gene therapy /
- adeno-associated virus

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参考文献(29)

[1]	Gouw SC, van den Berg HM, Fischer K, et al. Intensity of factor Ⅷ treatment and inhibitor development in children with severe hemophilia A: the RODIN study[J]. Blood, 2013, 121(20): 4046-4055. doi: 10.1182/blood-2012-09-457036
[2]	Reiss UM, Mahlangu J, Ohmori T, et al. Haemophilia gene therapy-Update on new country initiatives[J]. Haemophilia, 2022, 28 Suppl 4: 61-67.
[3]	Shirley JL, de Jong YP, Terhorst C, et al. Immune Responses to Viral Gene Therapy Vectors[J]. Mol Ther, 2020, 28(3): 709-722. doi: 10.1016/j.ymthe.2020.01.001
[4]	Kay MA, Manno CS, Ragni MV, et al. Evidence for gene transfer and expression of factor Ⅸ in haemophilia B patients treated with an AAV vector[J]. Nat Genet, 2000, 24(3): 257-261. doi: 10.1038/73464
[5]	Manno CS, Pierce GF, Arruda VR, et al. Successful transduction of liver in hemophilia by AAV-Factor Ⅸ and limitations imposed by the host immune response[J]. Nat Med, 2006, 12(3): 342-347. doi: 10.1038/nm1358
[6]	Nathwani AC, Tuddenham EG, Rangarajan S, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B[J]. N Engl J Med, 2011, 365(25): 2357-2365. doi: 10.1056/NEJMoa1108046
[7]	Nathwani AC, Reiss UM, Tuddenham EG, et al. Long-term safety and efficacy of factor Ⅸ gene therapy in hemophilia B[J]. N Engl J Med, 2014, 371(21): 1994-2004. doi: 10.1056/NEJMoa1407309
[8]	Miesbach W, Meijer K, Coppens M, et al. Gene therapy with adeno-associated virus vector 5-human factor Ⅸ in adults with hemophilia B[J]. Blood, 2018, 131(9): 1022-1031. doi: 10.1182/blood-2017-09-804419
[9]	George LA, Sullivan SK, Giermasz A, et al. Hemophilia B Gene Therapy with a High-Specific-Activity Factor Ⅸ Variant[J]. N Engl J Med, 2017, 377(23): 2215-2227. doi: 10.1056/NEJMoa1708538
[10]	Von Drygalski A, Giermasz A, Castaman G, et al. Etranacogene dezaparvovec(AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B[J]. Blood Adv, 2019, 3(21): 3241-3247. doi: 10.1182/bloodadvances.2019000811
[11]	Pipe SW, Recht M, Key NS, et al. First data from the phase 3 HOPE-B gene therapy trial: efficacy and safety of etranacogene dezaparvovec(AAV5-Padua hFIX variant; AMT-061) in adults with severe or moderate-severe hemophilia B treated irrespective of pre-existing anti-capsid neutralizing antibodies[J]. Blood, 2020, 136: LBA-6.
[12]	Rangarajan S, Walsh L, Lester W, et al. AAV5-Factor Ⅷ Gene Transfer in Severe Hemophilia A[J]. N Engl J Med, 2017, 377(26): 2519-2530. doi: 10.1056/NEJMoa1708483
[13]	Pasi KJ, Rangarajan S, Mitchell N, et al. Multiyear Follow-up of AAV5-hFⅧ-SQ Gene Therapy for Hemophilia A[J]. N Engl J Med, 2020, 382(1): 29-40. doi: 10.1056/NEJMoa1908490
[14]	Pasi KJ, Laffan M, Rangarajan S, et al. Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A[J]. Haemophilia, 2021, 27(6): 947-956. doi: 10.1111/hae.14391
[15]	Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A[J]. N Engl J Med, 2022, 386(11): 1013-1025. doi: 10.1056/NEJMoa2113708
[16]	Ozelo MC, Yamaguti-Hayakawa GG. Impact of novel hemophilia therapies around the world[J]. Res Pract Thromb Haemost, 2022, 6(3): e12695.
[17]	George LA, Monahan PE, Eyster ME, et al. Multiyear Factor Ⅷ Expression after AAV Gene Transfer for Hemophilia A[J]. N Engl J Med, 2021, 385(21): 1961-1973. doi: 10.1056/NEJMoa2104205
[18]	Pipe SW, Sheehan JP, Coppens M, et al. First-in-Human Dose-Finding Study of AAVhu37 Vector-Based Gene Therapy: BAY 2599023 Has Stable and Sustained Expression of FⅧ over 2 Years[J]. Blood, 2021, 138: 3971. doi: 10.1182/blood-2021-148661
[19]	Xue F, Li H, Wu X, et al. Safety and activity of an engineered, liver-tropic adeno-associated virus vector expressing a hyperactive Padua factor Ⅸ administered with prophylactic glucocorticoids in patients with haemophilia B: a single-centre, single-arm, phase 1, pilot trial[J]. Lancet Haematol, 2022 May 19;S2352-3026(22)00113-2. doi: 10.1016/S2352-3026(22)00113-2.Onlineaheadofprint.
[20]	Wu W, Xiao L, Wu X, et al. Factor Ⅸ alteration p. Arg338Gln(FIX Shanghai)potentiates FIX clotting activity and causes thrombosis[J]. Haematologica, 2021, 106(1): 264-268.
[21]	Wang HL, Gong J, Chung TH, et al. Lentiviral Gene Therapy for Hemophilia B: Exploration of Endothelial Promoters in Mesenchymal Stem Cells; proceedings of the MOLECULAR THERAPY, F, 2020[C]. CELL PRESS 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA.
[22]	Gong J, Chung TH, Wang HL, et al. Lentiviral Gene Therapy of Hemophilia A: Expression and Functional Comparison of Universal and Tissue-Specific Promoters; proceedings of the MOLECULAR THERAPY, F, 2020[C]. CELL PRESS 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA.
[23]	Stanford S, Pink R, Creagh D, et al. Adenovirus-associated antibodies in UK cohort of hemophilia patients: A seroprevalence study of the presence of adenovirus-associated virus vector-serotypes AAV5 and AAV8 neutralizing activity and antibodies in patients with hemophilia A[J]. Res Pract Thromb Haemost, 2019, 3(2): 261-267. doi: 10.1002/rth2.12177
[24]	Wang L, Calcedo R, Bell P, et al. Impact of pre-existing immunity on gene transfer to nonhuman primate liver with adeno-associated virus 8 vectors[J]. Hum Gene Ther, 2011, 22(11): 1389-1401. doi: 10.1089/hum.2011.031
[25]	Hurlbut GD, Ziegler RJ, Nietupski JB, et al. Preexisting immunity and low expression in primates highlight translational challenges for liver-directed AAV8-mediated gene therapy[J]. Mol Ther, 2010, 18(11): 1983-1994. doi: 10.1038/mt.2010.175
[26]	Nathwani AC, Gray JT, Mcintosh J, et al. Safe and efficient transduction of the liver after peripheral vein infusion of self-complementary AAV vector results in stable therapeutic expression of human FIX in nonhuman primates[J]. Blood, 2007, 109(4): 1414-1421. doi: 10.1182/blood-2006-03-010181
[27]	Mingozzi F, Anguela XM, Pavani G, et al. Overcoming preexisting humoral immunity to AAV using capsid decoys[J]. Sci Transl Med, 2013, 5(194): 194ra92.
[28]	Ohmori T. Advances in gene therapy for hemophilia: basis, current status, and future perspectives[J]. Int J Hematol, 2020, 111(1): 31-41. doi: 10.1007/s12185-018-2513-4
[29]	Everett LA, Cleuren AC, Khoriaty RN, et al. Murine coagulation factor Ⅷ is synthesized in endothelial cells[J]. Blood, 2014, 123(24): 3697-3705. doi: 10.1182/blood-2014-02-554501