综述

单基因遗传疾病的基因疗法

  • 周丽娟 ,
  • 王京春 ,
  • 高宏斌 ,
  • 赵东平
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  • 1. 中国科普研究所, 北京 100081;
    2. 中国科学院科技战略咨询研究院, 北京 100190
周丽娟,博士研究生,研究方向为药物筛选,电子信箱:zlj20077002@163.com

收稿日期: 2020-03-18

  修回日期: 2020-05-21

  网络出版日期: 2020-08-14

基金资助

国家重点研发计划项目(2019YFA0802104);国家自然科学基金重大项目(91954205)

Gene therapy for monogenetic diseases

  • ZHOU Lijuan ,
  • WANG Jingchun ,
  • GAO Hongbin ,
  • ZHAO Dongping
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  • 1. China Research Institute for Science Popularization, Beijing 100081, China;
    2. Institutes of Science and Development, Chinese Academy of Sciences, Beijing 100190, China

Received date: 2020-03-18

  Revised date: 2020-05-21

  Online published: 2020-08-14

摘要

基因疗法是全球突破性技术之一,在单基因遗传疾病治疗中已取得突破性进展。阐述了不同的基因疗法策略、载体和基因编辑技术的特点,综述了脊髓性肌萎缩症、Leber先天性黑蒙2型、血友病、β-地中海贫血的发病机理、临床表现、基因疗法的开发进程以及临床试验情况。目前,上述4种单基因疾病的9种基因疗法已分别取得美国食品药品监督管理局突破性疗法资格、欧洲药品管理局的优先药物资格或者已经批准上市。基因疗法的研究还面临着许多挑战,但随着科学研究的深入和科学技术的不断发展,将有更多的患者获得治疗。

本文引用格式

周丽娟 , 王京春 , 高宏斌 , 赵东平 . 单基因遗传疾病的基因疗法[J]. 科技导报, 2020 , 38(15) : 89 -100 . DOI: 10.3981/j.issn.1000-7857.2020.15.010

Abstract

Gene therapy is one of the world's breakthrough technologies, which has made breakthrough progress in the treatment of monogenic diseases. In this article the characteristics of different gene therapy strategies, vectors and gene editing techniques are described, with focuses on reviewing pathogenesis, clinical manifestations, development process of gene therapy and clinical trials of spinal muscular atrophy (SMA), Leber congenital amaurosis type 2 (LCA2), hemophilia, and β-thalassemia. At present, 9 gene therapies of the above 4 monogenic diseases have earned "breakthrough therapy" designation by the U.S. Food and Drug Administration (FDA), PRIME designation by the European Medicines Agency (EMA) or have been the gene therapies available on the market. The research of gene therapy faces many challenges but with the development of science and technology more patients will get treatment.

参考文献

[1] Eckhardt C L, van Velzen A S, Peters M, et al. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A[J]. Blood, 2013, 122(11):1954-1962.
[2] Lindvall K, von Mackensen S, Elmstahl S, et al. Increased burden on caregivers of having a child with haemophilia complicated by inhibitors[J]. Pediatr Blood Cancer, 2014, 61(4):706-711.
[3] Friedmann T, Robli R. Gene therapy for human genetic disease[J]. Science, 1972, 178(4061):648-649.
[4] Mansilla-Soto J, Riviere I, Boulad F, et al. Cell and gene therapy for the beta-Thalassemias:Advances and prospects[J]. Human Gene Therapy, 2016, 27(4):295-304.
[5] Naldini L. Gene therapy returns to centre stage[J]. Nature, 2015, 526(7573):351-360.
[6] Dunbar C E, High K A, Joung J K, et al. Gene therapy comes of age[J]. Science, 2018, 359(6372):1-10.
[7] Jenks S. Gene therapy death "everyone has to share in the guilt"[J]. Journal of the National Cancer Institute, 2000, 92(2):98-100.
[8] Rao V K, Kapp D, Schroth M. Gene therapy for spinal muscular atrophy:An emerging treatment option for a devastating disease[J]. Journal of Managed Care Specialty Pharmacy, 2018, 24(12):3-16.
[9] Brody H. Gene therapy[J]. Nature, 2018, 564(7735):5.
[10] Verma I M, Somia N. Gene therapy-Promises, problems and prospects[J]. Nature, 1997, 389(6648):239-242.
[11] Riviere I, Brose K, Mulligan R C. Effects of retroviral vector design on expression of human adenosine deaminase in murine bone marrow transplant recipients engrafted with genetically modified cells[J]. Proceedings of the National Academy of Sciences of the United States of America, 1995, 92(15):6733-6737.
[12] Halene S, Wang L, Cooper R M, et al. Improved expression in hematopoietic and lymphoid cells in mice after transplantation of bone marrow transduced with a modified retroviral vector[J]. Blood, 1999, 94(10):3349-3357.
[13] Naldini L. Ex vivo gene transfer and correction for cellbased therapies[J]. Nature Reviews Genetics, 2011, 12(5):301-315.
[14] Wu C, Dunbar C E. Stem cell gene therapy:The risks of insertional mutagenesis and approaches to minimize genotoxicity[J]. Frontiers of Medicine, 2011, 5(4):356-371.
[15] Montini E, Cesana D, Schmidt M, et al. The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy[J]. Journal of Clinical Investigation, 2009, 119(4):964-975.
[16] May C, Rivella S, Callegari J, et al. Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin[J]. Nature, 2000, 406(6791):82-86.
[17] Kosicki M, Tomberg K, Bradley A. Repair of doublestrand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements[J]. Nature Biotechnology, 2018, 36(8):765-771.
[18] Taruno A, Kashio M, Sun H, et al. Adeno-associated virus-mediated gene transfer into taste cells in vivo[J]. Chemical Senses, 2017, 42(1):69-78.
[19] Arruda V R, Samelson-Jones B J. Obstacles and future of gene therapy for hemophilia[J]. Expert Opinion on Orphan Drugs, 2015, 3(9):997-1010.
[20] Srivastava A. In vivo tissue-tropism of adeno-associated viral vectors[J]. Current Opinion in Virology, 2016, 21:75-80.
[21] Mendell J R, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy[J]. The New England Journal of Medicine, 2017, 377(18):1713-1722.
[22] Batty P, Lillicrap D. Advances and challenges for hemophilia gene therapy[J]. Human Molecular Genetics, 2019, 28(R1):R95-R101.
[23] Fonfara I, Le Rhun A, Chylinski K, et al. Phylogeny of Cas9 determines functional exchangeability of dualRNA and Cas9 among orthologous type II CRISPR-Cas systems[J]. Nucleic Acids Research, 2014, 42(4):2577-2590.
[24] Fisher R K, Mattern-Schain S I, Best M D, et al. Improving the efficacy of liposome-mediated vascular gene therapy via lipid surface modifications[J]. Journal of Surgical Research, 2017, 219:136-144.
[25] Dufes C, Uchegbu I F, Schatzlein A G. Dendrimers in gene delivery[J]. Advanced Drug Delivery Reviews, 2005, 57(15):2177-2202.
[26] Kim J S. Genome editing comes of age[J]. Nature Protocols, 2016, 11(9):1573-1578.
[27] Ishino Y, Shinagawa H, Makino K, et al. Nucleotide sequence of the iap gene, responsible for alkaline phosphatase isozyme conversion in Escherichia coli, and identification of the gene product[J]. Journal of Bacteriology, 1987, 169(12):5429-5433.
[28] Silva G, Poirot L, Galetto R, et al. Meganucleases and other tools for targeted genome engineering:Perspectives and challenges for gene therapy[J]. Current Gene Therapy, 2011, 11(1):11-27.
[29] Urnov F D, Rebar E J, Holmes M C, et al. Genome editing with engineered zinc finger nucleases[J]. Nature Reviews Genetics, 2010, 11(9):636-646.
[30] Lam K N, van Bakel H, Cote A G, et al. Sequence specificity is obtained from the majority of modular C2H2 zinc-finger arrays[J]. Nucleic Acids Research, 2011, 39(11):4680-4690.
[31] Ul Ain Q, Chung J Y, Kim Y H. Current and future delivery systems for engineered nucleases:ZFN, TALEN and RGEN[J]. Journal of Controlled Release, 2015, 205:120-127.
[32] Boch J, Scholze H, Schornack S, et al. Breaking the code of DNA binding specificity of TAL-type III effectors[J]. Science, 2009, 326(5959):1509-1512.
[33] Moscou M J, Bogdanove A J. A simple cipher governs DNA recognition by TAL effectors[J]. Science, 2009, 326(5959):1501.
[34] Gasiunas G, Barrangou R, Horvath P, et al. Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria[J]. Proceedings of the National Academy of Sciences of the United States of America, 2012, 109(39):2579-2586.
[35] Jinek M, Chylinski K, Fonfara I, et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity[J]. Science, 2012, 337(6096):816-821.
[36] Cho S W, Kim S, Kim Y, et al. Analysis of off-target effects of CRISPR/Cas-derived RNA-guided endonucleases and nickases[J]. Genome Research, 2014, 24(1):132-141.
[37] Kim D, Bae S, Park J, et al. Digenome-seq:Genomewide profiling of CRISPR-Cas9 off-target effects in human cells[J]. Nature Methods, 2015, 12(3):237-243.
[38] Komor A C, Kim Y B, Packer M S, et al. Programmable editing of a target base in genomic DNA without doublestranded DNA cleavage[J]. Nature, 2016, 533(7603):420-424.
[39] Lefebvre S, Burglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene[J]. Cell, 1995, 80(1):155-165.
[40] Sugarman E A, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy:Clinical laboratory analysis of >72, 400 specimens[J]. European Journal of Human Genetics, 2012, 20(1):27-32.
[41] Wirth B, Karakaya M, Kye M J, et al. Twenty-five years of spinal muscular atrophy research:From phenotype to genotype to therapy, and what comes next[J]. Annual Review of Genomics and Human Genetics, 2020.
[42] Foust K D, Wang X, McGovern V L, et al. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN[J]. Nature Biotechnology, 2010, 28(3):271-274.
[43] Dominguez E, Marais T, Chatauret N, et al. Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice[J]. Human Molecular Genetics, 2011, 20(4):681-693.
[44] Porensky P N, Burghes A H. Antisense oligonucleotides for the treatment of spinal muscular atrophy[J]. Human Molecular Genetics, 2013, 24(5):489-498.
[45] Talbot K, Tizzano E F. The clinical landscape for SMA in a new therapeutic era[J]. Gene Therapy, 2017, 24(9):529-533.
[46] Singh N K, Singh N N, Androphy E J, et al. Splicing of a critical exon of human Survival Motor Neuron is regulated by a unique silencer element located in the last intron[J]. Molecular and Cellular Biology, 2006, 26(4):1333-1346.
[47] Chung B H, Wong V, CIp P. Spinal muscular atrophy:Survival pattern and functional status[J]. Pediatrics, 2004, 114(5):548-553.
[48] Mercuri E, Darras B T, Chiriboga C A, et al. Nusinersen versus sham control in later-onset spinal muscular atrophy[J]. The New England Journal of Medicine, 2018, 378(7):625-635.
[49] Aartsma-Rus A. FDA Approval of nusinersen for spinal muscular atrophy makes 2016 the year of splice modulating oligonucleotides[J]. Nucleic Acid Therapeutics, 2017, 27(2):67-69.
[50] Meyer K, Ferraiuolo L, Schmelzer L, et al. Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA:A dose-response study in mice and nonhuman primates[J]. Molecular Therapy, 2015, 23(3):477-487.
[51] Hanein S, Perrault I, Gerber S, et al. Leber congenital amaurosis:Comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis[J]. Human Mutation, 2004, 23(4):306-317.
[52] Den Hollander A I, Roepman R, Koenekoop R K, et al. Leber congenital amaurosis:Genes, proteins and disease mechanisms[J]. Progress in Retinal and Eye Research, 2008, 27(4):391-419.
[53] Allikmets R. Leber congenital amaurosis:A genetic paradigm[J]. Ophthalmic Genetics, 2004, 25(2):67-79.
[54] Den Hollander A I. Omics in Ophthalmology:Advances in genomics and precision medicine for leber congenital amaurosis and age-related macular degeneration[J]. Investigative Ophthalmology & Visual Science, 2016, 57(3):1378-1387.
[55] Astuti G D, Bertelsen M, Preising M N, et al. Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark[J]. European Journal of Human Genetics, 2016, 24(7):1071-1079.
[56] Moore N A, Morral N, Ciulla T A, et al. Gene therapy for inherited retinal and optic nerve degenerations[J]. Expert Opinion on Biological Therapy, 2018, 18(1):37-49.
[57] Russell S, Bennett J, Wellman J A, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy:A randomised, controlled, open-label, phase 3 trial[J]. Lancet, 2017, 390(10097):849-860.
[58] Wu B X, Moiseyev G, Chen Y, et al. Identification of RDH10, an All-trans Retinol Dehydrogenase, in Retinal Muller Cells[J]. Investigative Ophthalmology & Visual Science, 2004, 45(11):3857-3862.
[59] Bennett J, Wellman J, Marshall K A, et al. Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations:A follow-on phase 1 trial[J]. Lancet, 2016, 388(10045):661-672.
[60] Bennicelli J, Wright J F, Komaromy A, et al. Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer[J]. Molecular Therapy, 2008, 16(3):458-465.
[61] Maguire A M, Simonelli F, Pierce E A, et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis[J]. The New England Journal of Medicine, 2008, 358(21):2240-2248.
[62] Ashtari M, Cyckowski L L, Monroe J F, et al. The human visual cortex responds to gene therapy-mediated recovery of retinal function[J]. Journal of Clinical Investigation, 2011, 121(6):2160-2168.
[63] Ashtari M, Zhang H, Cook P A, et al. Plasticity of the human visual system after retinal gene therapy in patients with Leber's congenital amaurosis[J]. Science Translational Medicine, 2015, 7(296):96-110.
[64] Bainbridge J W, Smith A J, Barker S S, et al. Effect of gene therapy on visual function in Leber's congenital amaurosis[J]. The New England Journal of Medicine, 2008, 358(21):2231-2239.
[65] Maguire A M, High K A, Auricchio A, et al. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis:A phase 1 dose-escalation trial[J]. Lancet, 2009, 374(9701):1597-1605.
[66] Mannucci P M, Tuddenham E G. The hemophilias from royal genes to gene therapy[J]. The New England Journal of Medicine, 2001, 344(23):1773-1779.
[67] Brackman H H. Hemophilia home treatment in West Germany[J]. Scand J Haematol Suppl, 1977, 31:11-15.
[68] Jones P K, Ratnoff O D. The changing prognosis of classic hemophilia (factor VIII "deficiency")[J]. Annals of Internal Medicine, 1991, 114(8):641-648.
[69] Khaliavina I N, Gileva O S, Plenkina Iu A, et al. Guidelines for dental care in hemophilia patients[J]. Stomatologiia (Mosk), 2012, 91(2):9-11.
[70] Skinner M W. WFH:Closing the global gap——achieving optimal care[J]. Haemophilia, 2012, 18(Suppl 4):1-12.
[71] Herzog R W, Hagstrom J N, Kung S H, et al. Stable gene transfer and expression of human blood coagulation factor IX after intramuscular injection of recombinant adeno-associated virus[J]. Proceedings of the National Academy of Sciences of the United States of America, 1997, 94(11):5804-5809.
[72] Mount J D, Herzog R W, Tillson D M, et al. Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy[J]. Blood, 2002, 99(8):2670-2676.
[73] Manno C S, Chew A J, Hutchison S, et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B[J]. Blood, 2003, 101(8):2963-2972.
[74] Manno C S, Pierce G F, Arruda V R, et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response[J]. Nature Medicine, 2006, 12(3):342-347.
[75] Buchlis G, Podsakoff G M, Radu A, et al. Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer[J]. Blood, 2012, 119(13):3038-3041.
[76] High K A. Gene therapy for hemophilia:The clot thickens[J]. Human Gene Therapy, 2014, 25(11):915-922.
[77] Nathwani A C, Davidoff A M, Tuddenham G D. Advances in Gene Therapy for Hemophilia[J]. Human Gene Therapy, 2017, 28(11):1004-1012.
[78] Chang A H, Stephan M T, Sadelain M. Stem cell-derived erythroid cells mediate long-term systemic protein delivery[J]. Nature Biotechnology, 2006, 24(8):1017-1021.
[79] Rangarajan S, Walsh L, Lester W, et al. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A[J]. The New England Journal of Medicine, 2017, 377(26):2519-2530.
[80] Gollomp K L, Doshi B S, Arruda V R. Gene therapy for hemophilia:Progress to date and challenges moving forward[J]. Transfusion and Apheresis Science, 2019, 58(5):602-612.
[81] Mingozzi F, High K A. Immune responses to AAV vectors:overcoming barriers to successful gene therapy[J]. Blood, 2013, 122(1):23-36.
[82] Mimuro J, Mizukami H, Shima M, et al. The prevalence of neutralizing antibodies against adeno-associated virus capsids is reduced in young Japanese individuals[J]. Journal of Medical Virology, 2014, 86(11):1990-1997.
[83] Roth C K, Puttbrese A, Ottley C. Thalassemia Syndromes in Pregnancy[J]. Nursing for Women's Health, 2016, 20(4):415-420.
[84] Rund D, Rachmilewitz E. Beta-thalassemia[J]. The New England Journal of Medicine, 2005, 353(11):1135-1146.
[85] Vichinsky E P. Changing patterns of thalassemia worldwide[J]. Annals of The New York Academy of Sciences, 2005, 1054:18-24.
[86] May C, Rivella S, Chadburn A, et al. Successful treatment of murine beta-thalassemia intermedia by transfer of the human beta-globin gene[J]. Blood, 2002, 99(6):1902-1908.
[87] Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia[J]. Nature, 2010, 467(7313):318-322.
[88] Dever D P, Porteus M H. The changing landscape of gene editing in hematopoietic stem cells:A step towards Cas9 clinical translation[J]. Current Opinion in Hematology, 2017, 24(6):481-488.
[89] Thompson A A, Walters M C, Kwiatkowski J, et al. Gene Therapy in Patients with Transfusion-Dependent beta-Thalassemia[J]. The New England Journal of Medicine, 2018, 378(16):1479-1493.
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