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An overview of development in gene therapeutics in China

Gene Therapy volume 27, pages 338–348 (2020)Cite this article

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Abstract

After setbacks related to serious adverse events 20 years ago, gene therapy is now coming back to the central stage worldwide. In the past few years, gene therapy has shown astonishing efficacy against genetic diseases and cancers. In history, China carried out the world’s second gene therapy clinical trial in 1991 for hemophilia B and approved the world’s first gene therapy product—Gendicine—in 2003. In recent years, numerous efforts have been made on gene editing. Here, we reviewed the past of gene therapy in China and highlighted recent advances. We also discussed the regulations and future perspectives of gene therapy in China.

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Fig. 1: Milestones of gene therapy in China.

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References

  1. Friedmann T, Roblin R. Gene therapy for human genetic disease? Science. 1972;175:949–55.

    CAS  PubMed  Google Scholar 

  2. Shimotohno K, Temin HM. Formation of infectious progeny virus after insertion of herpes simplex thymidine kinase gene into DNA of an avian retrovirus. Cell. 1981;26:67–77.

    CAS  PubMed  Google Scholar 

  3. Wei CM, Gibson M, Spear PG, Scolnick EM. Construction and isolation of a transmissible retrovirus containing the src gene of Harvey murine sarcoma virus and the thymidine kinase gene of herpes simplex virus type 1. J Virol. 1981;39:935–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Tabin CJ, Hoffmann JW, Goff SP, Weinberg RA. Adaptation of a retrovirus as a eucaryotic vector transmitting the herpes simplex virus thymidine kinase gene. Mol Cell Biol. 1982;2:426–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao GP, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab. 2003;80:148–58.

    CAS  PubMed  Google Scholar 

  6. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003;302:415–9.

    CAS  PubMed  Google Scholar 

  7. Hacein-Bey-Abina S, Garrigue A, Wang GP, Soulier J, Lim A, Morillon E, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Investig. 2008;118:3132–42.

    CAS  PubMed  Google Scholar 

  8. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science. 2000;288:669–72.

    CAS  PubMed  Google Scholar 

  9. Dunbar CE, High KA, Joung JK, Kohn DB, Ozawa K, Sadelain M. Gene therapy comes of age. Science. 2018;359:eaan4672.

    PubMed  Google Scholar 

  10. Hoggatt J. Gene therapy for “Bubble Boy” disease. Cell. 2016;166:263.

    CAS  PubMed  Google Scholar 

  11. Blaese RM, Anderson WF. The ADA human gene therapy clinical protocol original covering Memo: February 23, 1990. Hum Gene Ther. 1990;1:327–9.

    Google Scholar 

  12. Lu DR, Zhou JM, Zheng B, Qiu XF, Xue JL, Wang JM, et al. Stage I clinical trial of gene therapy for hemophilia B. Sci China B. 1993;36:1342–51.

    CAS  PubMed  Google Scholar 

  13. Cyranoski D. CRISPR gene-editing tested in a person for the first time. Nature. 2016;539:479.

    CAS  PubMed  Google Scholar 

  14. Cyranoski D, Ledford H. Genome-edited baby claim provokes international outcry. Nature. 2018;563:607–8.

    CAS  PubMed  Google Scholar 

  15. Berntorp E, Shapiro AD. Modern haemophilia care. Lancet. 2012;379:1447–56.

    PubMed  Google Scholar 

  16. Qiu X, Lu D, Zhou J, Wang J, Yang J, Meng P, et al. Implantation of autologous skin fibroblast genetically modified to secrete clotting factor IX partially corrects the hemorrhagic tendencies in two hemophilia B patients. Chin Med J. 1996;109:832–9.

    CAS  PubMed  Google Scholar 

  17. Qiu XF, Lu DR, Xue HWW, Yang JL, Meng JM, Clinical PL. trials of gene therapy in four patients with hemophilia B (in Chinese). J Fudan Univ (Nat Sci). 1996;35:341–8.

    CAS  Google Scholar 

  18. Qu Y, Nie X, Yang Z, Yin H, Pang Y, Dong P, et al. The prevalence of hemophilia in mainland China: a systematic review and meta-analysis. Southeast Asian J Trop Med Public Health. 2014;45:455–66.

    PubMed  Google Scholar 

  19. Rangarajan S, Walsh L, Lester W, Perry D, Madan B, Laffan M, et al. AAV5-factor VIII gene transfer in severe hemophilia A. N Engl J Med. 2017;377:2519–30.

    CAS  PubMed  Google Scholar 

  20. George LA, Sullivan SK, Giermasz A, Rasko JEJ, Samelson-Jones BJ, Ducore J, et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med. 2017;377:2215–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014;371:1994–2004.

    PubMed  PubMed Central  Google Scholar 

  22. Pasi KJ, Rangarajan S, Mitchell N, Lester W, Symington E, Madan B, et al. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N Engl J Med. 2020;382:29–40.

    CAS  PubMed  Google Scholar 

  23. Guan Y, Ma Y, Li Q, Sun Z, Ma L, Wu L, et al. CRISPR/Cas9-mediated somatic correction of a novel coagulator factor IX gene mutation ameliorates hemophilia in mouse. EMBO Mol Med. 2016;8:477–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Stephens CJ, Lauron EJ, Kashentseva E, Lu ZH, Yokoyama WM, Curiel DT. Long-term correction of hemophilia B using adenoviral delivery of CRISPR/Cas9. J Control Release. 2019;298:128–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Huai C, Jia C, Sun R, Xu P, Min T, Wang Q, et al. CRISPR/Cas9-mediated somatic and germline gene correction to restore hemostasis in hemophilia B mice. Hum Genet. 2017;136:875–83.

    CAS  PubMed  Google Scholar 

  26. Wang D, Zhang G, Gu J, Shao X, Dai Y, Li J, et al. In vivo generated hematopoietic stem cells from genome edited induced pluripotent stem cells are functional in platelet-targeted gene therapy of murine hemophilia A. Haematologica. 2020;105:e175–9.

    PubMed  PubMed Central  Google Scholar 

  27. Li SJ, Luo Y, Zhang LM, Yang W, Zhang GG. Targeted introduction and effective expression of hFIX at the AAVS1 locus in mesenchymal stem cells. Mol Med Rep. 2017;15:1313–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, et al. Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature. 2010;467:318–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Yang G, Shi W, Hu X, Zhang J, Gong Z, Guo X, et al. Therapeutic effects of induced pluripotent stem cells in chimeric mice with beta-thalassemia. Haematologica. 2014;99:1304–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhou YJ, Xie DN. Progress in the prevention and treatment of beta-thalassemia. Chin J Fam Plan. 2015;23:P709–13.

    Google Scholar 

  31. Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, Ribeil JA, Hongeng S, et al. Gene therapy in patients with transfusion-dependent beta-thalassemia. N Engl J Med. 2018;378:1479–93.

    CAS  PubMed  Google Scholar 

  32. Marktel S, Scaramuzza S, Cicalese MP, Giglio F, Galimberti S, Lidonnici MR, et al. Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent ss-thalassemia. Nat Med. 2019;25:234–41.

    CAS  PubMed  Google Scholar 

  33. Tian J, Wang F, Xue JF, Zhao F, Zhong M, Song LJ, et al. Recombinant adeno-associated virus 2-mediated gene therapy for β-thalassemia. J Shanghai Jiaotong Univ (Med Sci). 2011;31:9–14.

    Google Scholar 

  34. Wang L, Li L, Ma Y, Hu H, Li Q, Yang Y et al. Reactivation of γ-globin expression through Cas9 or base editor to treat β-hemoglobinopathies. Cell Res. 2020;30:276–8.

    PubMed  Google Scholar 

  35. Lu Y, Xue J, Deng T, Zhou X, Yu K, Deng L, et al. Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer. Nat Med. 2020;26:732–40.

    CAS  PubMed  Google Scholar 

  36. Xu L, Wang J, Liu Y, Xie L, Su B, Mou D, et al. CRISPR-edited stem cells in a patient with HIV and acute lymphocytic leukemia. N Engl J Med. 2019;381:1240–7.

    CAS  PubMed  Google Scholar 

  37. Liang P, Xu Y, Zhang X, Ding C, Huang R, Zhang Z, et al. CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell. 2015;6:363–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang H, Yang H. Gene-edited babies: What went wrong and what could go wrong. PLoS Biol. 2019;17:e3000224.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Cyranoski D. Russian ‘CRISPR-baby’ scientist has started editing genes in human eggs with goal of altering deaf gene. Nature. 2019;574:465–6.

    CAS  PubMed  Google Scholar 

  40. Porteus MH, Baltimore D. Chimeric nucleases stimulate gene targeting in human cells. Science. 2003;300:763.

    PubMed  Google Scholar 

  41. Stoddard BL. Homing endonuclease structure and function. Q Rev Biophys. 2005;38:49–95.

    CAS  PubMed  Google Scholar 

  42. Briggs AW, Rios X, Chari R, Yang L, Zhang F, Mali P, et al. Iterative capped assembly: rapid and scalable synthesis of repeat-module DNA such as TAL effectors from individual monomers. Nucleic Acids Res. 2012;40:e117.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Bedell VM, Wang Y, Campbell JM, Poshusta TL, Starker CG, Krug RG 2nd, et al. In vivo genome editing using a high-efficiency TALEN system. Nature. 2012;491:114–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Makarova KS, Zhang F, Koonin EV. SnapShot: Class 1 CRISPR-Cas Systems. Cell. 2017;168:946–946 e1.

    CAS  PubMed  Google Scholar 

  45. Liu L, Chen P, Wang M, Li X, Wang J, Yin M, et al. C2c1-sgRNA complex structure reveals RNA-guided DNA cleavage mechanism. Mol. Cell. 2017;65:310–22.

    CAS  PubMed  Google Scholar 

  46. Shmakov S, Abudayyeh OO, Makarova KS, Wolf YI, Gootenberg JS, Semenova E, et al. Discovery and functional characterization of diverse Class 2 CRISPR-Cas Systems. Mol Cell. 2015;60:385–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Teng F, Cui T, Feng G, Guo L, Xu K, Gao Q, et al. Repurposing CRISPR-Cas12b for mammalian genome engineering. Cell Discov. 2018;4:63.

    PubMed  PubMed Central  Google Scholar 

  48. Strecker J, Jones S, Koopal B, Schmid-Burgk J, Zetsche B, Gao L, et al. Engineering of CRISPR-Cas12b for human genome editing. Nat Commun. 2019;10:212.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016;533:420–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Komor AC, Zhao KT, Packer MS, Gaudelli NM, Waterbury AL, Koblan LW, et al. Improved base excision repair inhibition and bacteriophage Mu Gam protein yields C:G-to-T:A base editors with higher efficiency and product purity. Sci Adv. 2017;3:eaao4774.

    PubMed  PubMed Central  Google Scholar 

  51. Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, et al. Programmable base editing of A*T to G*C in genomic DNA without DNA cleavage. Nature. 2017;551:464–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Li X, Wang Y, Liu Y, Yang B, Wang X, Wei J, et al. Base editing with a Cpf1-cytidine deaminase fusion. Nat Biotechnol. 2018;36:324–7.

    CAS  PubMed  Google Scholar 

  53. Wang X, Li J, Wang Y, Yang B, Wei J, Wu J, et al. Efficient base editing in methylated regions with a human APOBEC3A-Cas9 fusion. Nat Biotechnol. 2018;36:946–9.

    CAS  PubMed  Google Scholar 

  54. Zuo E, Sun Y, Wei W, Yuan T, Ying W, Sun H, et al. Cytosine base editor generates substantial off-target single-nucleotide variants in mouse embryos. Science. 2019;364:289–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Naldini L, Trono D, Verma IM. Lentiviral vectors, two decades later. Science. 2016;353:1101–2.

    CAS  PubMed  Google Scholar 

  56. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009;326:818–23.

    CAS  PubMed  Google Scholar 

  57. Naldini L. Gene therapy returns to centre stage. Nature. 2015;526:351–60.

    CAS  PubMed  Google Scholar 

  58. Blaese RM, Culver KW, Miller AD, Carter CS, Fleisher T, Clerici M, et al. T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Science. 1995;270:475–80.

    CAS  PubMed  Google Scholar 

  59. Yuan J, Zhang Y, Liu H, Wang D, Du Y, Tian Z et al. Seven-year follow-up of gene therapy for Leber’s hereditary optic neuropathy. Ophthalmology. 2020. https://doi.org/10.1016/j.ophtha.2020.02.023.

  60. Wan X, Pei H, Zhao MJ, Yang S, Hu WK, He H, et al. Efficacy and safety of rAAV2-ND4 treatment for Leber’s hereditary optic neuropathy. Sci Rep. 2016;6:21587.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Liu HL, Yuan JJ, Zhang Y, Tian Z, Li X, Wang D et al. Factors associated with rapid improvement in visual acuity in patients with Leber’s hereditary optic neuropathy after gene therapy. Acta Ophthalmol. 2020. https://doi.org/10.1111/aos.14379.

  62. Valdmanis PN, Lisowski L, Kay MA. rAAV-mediated tumorigenesis: still unresolved after an AAV assault. Mol. Ther. 2012;20:2014–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Kaiser J. How safe is a popular gene therapy vector? Science. 2020;367:131.

    CAS  PubMed  Google Scholar 

  64. Lv J, He B, Yu J, Wang Y, Wang C, Zhang S, et al. Fluoropolymers for intracellular and in vivo protein delivery. Biomaterials. 2018;182:167–75.

    CAS  PubMed  Google Scholar 

  65. Liu C, Wan T, Wang H, Zhang S, Ping Y, Cheng Y. A boronic acid-rich dendrimer with robust and unprecedented efficiency for cytosolic protein delivery and CRISPR-Cas9 gene editing. Sci Adv. 2019;5:eaaw8922.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Yin D, Ling S, Tian X, Li Y, Xu Z, Jiang H, et al. A single dose SARS-CoV-2 simulating particle vaccine induces potent neutralizing activities. bioRxiv. 2020: 2020.05.14.093054.

  67. Bischoff JR, Kirn DH, Williams A, Heise C, Horn S, Muna M, et al. An Adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science. 1996;274:373.

    CAS  PubMed  Google Scholar 

  68. Zhang W-W, Li L, Li D, Liu J, Li X, Li W, et al. The first approved gene therapy product for cancer Ad-p53 (Gendicine): 12 years in the clinic. Hum Gene Ther. 2018;29:160–79.

    CAS  PubMed  Google Scholar 

  69. Liang M. Oncorine, the world first oncolytic virus medicine and its update in China. Curr Cancer Drug Targets. 2018;18:171–6.

    CAS  PubMed  Google Scholar 

  70. Lin Y, Zhang H, Liang J, Li K, Zhu W, Fu L, et al. Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers. Proc Natl Acad Sci USA. 2014;111:E4504–12.

    CAS  PubMed  Google Scholar 

  71. Zhang H, Li K, Lin Y, Xing F, Xiao X, Cai J, et al. Targeting VCP enhances anticancer activity of oncolytic virus M1 in hepatocellular carcinoma. Sci. Transl. Med. 2017;9:eaam7996.

    PubMed  Google Scholar 

  72. Zhu Y, Hu X, Feng L, Yang Z, Zhou L, Duan X, et al. Enhanced therapeutic efficacy of a novel oncolytic herpes simplex virus Type 2 encoding an antibody against programmed cell death 1. Mol Ther Oncolytics. 2019;15:201–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Wu C, Wu M, Liang M, Xiong S, Dong C. A novel oncolytic virus engineered with PD-L1 scFv effectively inhibits tumor growth in a mouse model. Cell Mol Immunol. 2019;16:780–2.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang Y, Jin J, Wu Z, Hu S, Hu H, Ning Z, et al. Stability and anti-tumor effect of oncolytic herpes simplex virus type 2. Oncotarget. 2018;9:24672–83.

    PubMed  PubMed Central  Google Scholar 

  75. Mao LJ, Ding M, Xu K, Pan J, Yu H, Yang C. Oncolytic adenovirus harboring interleukin-24 improves chemotherapy for advanced prostate cancer. J Cancer. 2018;9:4391–7.

    PubMed  PubMed Central  Google Scholar 

  76. Meng G, Li B, Chen A, Zheng M, Xu T, Zhang H, et al. Targeting aerobic glycolysis by dichloroacetate improves Newcastle disease virus-mediated viro-immunotherapy in hepatocellular carcinoma. Br J Cancer. 2020;122:111–120.

    CAS  PubMed  Google Scholar 

  77. Gao H, Zhang X, Ding Y, Qiu R, Hong Y, Chen W. Synergistic suppression effect on tumor growth of colorectal cancer by combining radiotherapy with a TRAIL-armed oncolytic Adenovirus. Technol Cancer Res Treat. 2019;18:1533033819853290.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Lv P, Liu X, Chen X, Liu C, Zhang Y, Chu C, et al. Genetically engineered cell membrane nanovesicles for oncolytic Adenovirus delivery: a versatile platform for cancer virotherapy. Nano Lett. 2019;19:2993–3001.

    CAS  PubMed  Google Scholar 

  79. Huang H, Liu Y, Liao W, Cao Y, Liu Q, Guo Y, et al. Oncolytic adenovirus programmed by synthetic gene circuit for cancer immunotherapy. Nat Commun. 2019;10:4801.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

YC is supported by National Natural Science Foundation of China [31971364]; Pujiang Talent Project of Shanghai [GJ4150006]; Natural Science Foundation of Shanghai [BS4150002]; Startup funding from Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University [WF220441504].

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  1. National Research Center for Translational Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Dawei Wang

  2. School of Law, Shanghai University of Political Science and Law, Shanghai, 201701, China

    Kang Wang

  3. Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China

    Yujia Cai

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Wang, D., Wang, K. & Cai, Y. An overview of development in gene therapeutics in China. Gene Ther 27, 338–348 (2020). https://doi.org/10.1038/s41434-020-0163-7

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