Login Register Cart 0
Review Article

AAV衣壳基因的基因工程在基因治疗中的应用

卷 20, 期 5, 2020

页: [321 - 332] 页: 12

弟呕挨: 10.2174/1566523220666200930105521

价格: $65

摘要

腺相关病毒（AAV）由于其出色的安全性和介导人类受试者稳定基因表达的能力而成为体内基因治疗的有前途的载体。 但是，在将该基因递送载体用于临床应用之前，仍然需要解决许多挑战，例如AAV无法有效地靶向特定组织，人类人群中预先存在的中和抗体以及AAV包装能力有限。 在过去的二十年中，对AAV衣壳基因进行了大量的遗传修饰工作，从而产生了大量具有修饰特征的变体，从而使AAV成为了一种通用载体，可以更有效地用于不同遗传疾病的基因治疗应用。

关键词: 腺相关病毒，衣壳基因，遗传修饰，组织嗜性，中和抗体，DNA。

Next »
图形摘要

[1]
Atchison RW, Casto BC, Hammon WMD. Adenovirus-associated defective virus particles. Science 1965; 149(3685): 754-6.
[http://dx.doi.org/10.1126/science.149.3685.754] [PMID: 14325163]
[2]
Koczot FJ, Carter BJ, Garon CF, Rose JA. Self-complementarity of terminal sequences within plus or minus strands of adenovirus-associated virus DNA. Proc Natl Acad Sci USA 1973; 70(1): 215-9.
[http://dx.doi.org/10.1073/pnas.70.1.215] [PMID: 4509654]
[3]
Gonçalves M A FV. Adeno-associated virus: from defective virus to effective vector. Virol J 2005; 2: 43-59.
[http://dx.doi.org/10.1186/1743-422X-2-43] [PMID: 15877812]
[4]
Sonntag F, Schmidt K, Kleinschmidt JA. A viral assembly factor promotes AAV2 capsid formation in the nucleolus. Proc Natl Acad Sci USA 2010; 107(22): 10220-5.
[http://dx.doi.org/10.1073/pnas.1001673107] [PMID: 20479244]
[5]
Naumer M, Sonntag F, Schmidt K, et al. Properties of the adeno-associated virus assembly-activating protein. J Virol 2012; 86(23): 13038-48.
[http://dx.doi.org/10.1128/JVI.01675-12] [PMID: 23015698]
[6]
Wu Z, Yang H, Colosi P. Effect of genome size on AAV vector packaging. Mol Ther 2010; 18(1): 80-6.
[http://dx.doi.org/10.1038/mt.2009.255] [PMID: 19904234]
[7]
Darrow JJ. Luxturna: FDA documents reveal the value of a costly gene therapy. Drug Discov Today 2019; 24(4): 949-54.
[http://dx.doi.org/10.1016/j.drudis.2019.01.019] [PMID: 30711576]
[8]
Keeler AM, Flotte TR. Recombinant adeno-associated virus gene therapy in light of Luxturna (and Zolgensma and Glybera): where are we, and how did we get here? Annu Rev Virol 2019; 6(1): 601-21.
[http://dx.doi.org/10.1146/annurev-virology-092818-015530] [PMID: 31283441]
[9]
George LA, Sullivan SK, Giermasz A, et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med 2017; 377(23): 2215-27.
[http://dx.doi.org/10.1056/NEJMoa1708538] [PMID: 29211678]
[10]
Duan D. Micro-dystrophin gene therapy goes systemic in Duchenne muscular dystrophy patients. Hum Gene Ther 2018; 29(7): 733-6.
[http://dx.doi.org/10.1089/hum.2018.012] [PMID: 29463117]
[11]
Ding W, Zhang L, Yan Z, Engelhardt JF. Intracellular trafficking of adeno-associated viral vectors. Gene Ther 2005; 12(11): 873-80.
[http://dx.doi.org/10.1038/sj.gt.3302527] [PMID: 15829993]
[12]
Pillay S, Meyer NL, Puschnik AS, et al. An essential receptor for adeno-associated virus infection. Nature 2016; 530(7588): 108-12.
[http://dx.doi.org/10.1038/nature16465] [PMID: 26814968]
[13]
Dudek AM, Pillay S, Puschnik AS, et al. An alternate route for Adeno-associated Virus (AAV) entry independent of AAV receptor. J Virol 2018; 92(7): e02213-7.
[http://dx.doi.org/10.1128/JVI.02213-17] [PMID: 29343568]
[14]
Nonnenmacher M, Weber T. Intracellular transport of recombinant adeno-associated virus vectors. Gene Ther 2012; 19(6): 649-58.
[http://dx.doi.org/10.1038/gt.2012.6] [PMID: 22357511]
[15]
Sonntag F, Bleker S, Leuchs B, Fischer R, Kleinschmidt JA. Adeno-associated virus type 2 capsids with externalized VP1/VP2 trafficking domains are generated prior to passage through the cytoplasm and are maintained until uncoating occurs in the nucleus. J Virol 2006; 80(22): 11040-54.
[http://dx.doi.org/10.1128/JVI.01056-06] [PMID: 16956943]
[16]
Dudek AM, Zabaleta N, Zinn E, et al. GPR108 is a highly conserved AAV entry factor. Mol Ther 2020; 28(2): 367-81.
[http://dx.doi.org/10.1016/j.ymthe.2019.11.005] [PMID: 31784416]
[17]
Xiao W, Warrington KH Jr, Hearing P, Hughes J, Muzyczka N. Adenovirus-facilitated nuclear translocation of adeno-associated virus type 2. J Virol 2002; 76(22): 11505-17.
[http://dx.doi.org/10.1128/JVI.76.22.11505-11517.2002] [PMID: 12388712]
[18]
Nicolson SC, Samulski RJ. Recombinant adeno-associated virus utilizes host cell nuclear import machinery to enter the nucleus. J Virol 2014; 88(8): 4132-44.
[http://dx.doi.org/10.1128/JVI.02660-13] [PMID: 24478436]
[19]
Duan D, Sharma P, Yang J, et al. Circular intermediates of recombinant adeno-associated virus have defined structural characteristics responsible for long-term episomal persistence in muscle tissue. J Virol 1998; 72(11): 8568-77.
[http://dx.doi.org/10.1128/JVI.72.11.8568-8577.1998] [PMID: 9765395]
[20]
Hansen J, Qing K, Srivastava A. Infection of purified nuclei by adeno-associated virus 2. Mol Ther 2001; 4(4): 289-96.
[http://dx.doi.org/10.1006/mthe.2001.0457] [PMID: 11592830]
[21]
Xie Q, Bu W, Bhatia S, et al. The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy. Proc Natl Acad Sci USA 2002; 99(16): 10405-10.
[http://dx.doi.org/10.1073/pnas.162250899] [PMID: 12136130]
[22]
Girod A, Ried M, Wobus C, et al. Genetic capsid modifications allow efficient re-targeting of adeno-associated virus type 2. Nat Med 1999; 5(9): 1052-6.
[http://dx.doi.org/10.1038/12491] [PMID: 10470084]
[23]
Nicklin SA, Buening H, Dishart KL, et al. Efficient and selective AAV2-mediated gene transfer directed to human vascular endothelial cells. Mol Ther 2001; 4(3): 174-81.
[http://dx.doi.org/10.1006/mthe.2001.0424] [PMID: 11545607]
[24]
White SJ, Nicklin SA, Büning H, et al. Targeted gene delivery to vascular tissue in vivo by tropism-modified adeno-associated virus vectors. Circulation 2004; 109(4): 513-9.
[http://dx.doi.org/10.1161/01.CIR.0000109697.68832.5D] [PMID: 14732747]
[25]
Work LM, Nicklin SA, Brain NJR, et al. Development of efficient viral vectors selective for vascular smooth muscle cells. Mol Ther 2004; 9(2): 198-208.
[http://dx.doi.org/10.1016/j.ymthe.2003.11.006] [PMID: 14759804]
[26]
Grifman M, Trepel M, Speece P, et al. Incorporation of tumor-targeting peptides into recombinant adeno-associated virus capsids. Mol Ther 2001; 3(6): 964-75.
[http://dx.doi.org/10.1006/mthe.2001.0345] [PMID: 11407911]
[27]
Asokan A, Conway JC, Phillips JL, et al. Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle. Nat Biotechnol 2010; 28(1): 79-82.
[http://dx.doi.org/10.1038/nbt.1599] [PMID: 20037580]
[28]
Shen S, Horowitz ED, Troupes AN, et al. Engraftment of a galactose receptor footprint onto adeno-associated viral capsids improves transduction efficiency. J Biol Chem 2013; 288(40): 28814-23.
[http://dx.doi.org/10.1074/jbc.M113.482380] [PMID: 23940044]
[29]
Bowles DE, McPhee SWJ, Li C, et al. Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Mol Ther 2012; 20(2): 443-55.
[http://dx.doi.org/10.1038/mt.2011.237] [PMID: 22068425]
[30]
Zhong L, Li B, Jayandharan G, et al. Tyrosine-phosphorylation of AAV2 vectors and its consequences on viral intracellular trafficking and transgene expression. Virology 2008; 381(2): 194-202.
[http://dx.doi.org/10.1016/j.virol.2008.08.027] [PMID: 18834608]
[31]
Zhong L, Li B, Mah CS, et al. Next generation of adeno-associated virus 2 vectors: point mutations in tyrosines lead to high-efficiency transduction at lower doses. Proc Natl Acad Sci USA 2008; 105(22): 7827-32.
[http://dx.doi.org/10.1073/pnas.0802866105] [PMID: 18511559]
[32]
Wang D, Li S, Gessler DJ, et al. A Rationally engineered capsid variant of AAV9 for systemic CNS-directed and peripheral tissue-detargeted gene delivery in neonates. Mol Ther Methods Clin Dev 2018; 9: 234-46.
[http://dx.doi.org/10.1016/j.omtm.2018.03.004] [PMID: 29766031]
[33]
Packer MS, Liu DR. Methods for the directed evolution of proteins. Nat Rev Genet 2015; 16(7): 379-94.
[http://dx.doi.org/10.1038/nrg3927] [PMID: 26055155]
[34]
Maheshri N, Koerber JT, Kaspar BK, Schaffer DV. Directed evolution of adeno-associated virus yields enhanced gene delivery vectors. Nat Biotechnol 2006; 24(2): 198-204.
[http://dx.doi.org/10.1038/nbt1182] [PMID: 16429148]
[35]
Asuri P, Bartel MA, Vazin T, Jang JH, Wong TB, Schaffer DV. Directed evolution of adeno-associated virus for enhanced gene delivery and gene targeting in human pluripotent stem cells. Mol Ther 2012; 20(2): 329-38.
[http://dx.doi.org/10.1038/mt.2011.255] [PMID: 22108859]
[36]
Crameri A, Raillard SA, Bermudez E, Stemmer WP. DNA shuffling of a family of genes from diverse species accelerates directed evolution. Nature 1998; 391(6664): 288-91.
[http://dx.doi.org/10.1038/34663] [PMID: 9440693]
[37]
Gao G, Alvira MR, Somanathan S, et al. Adeno-associated viruses undergo substantial evolution in primates during natural infections. Proc Natl Acad Sci USA 2003; 100(10): 6081-6.
[http://dx.doi.org/10.1073/pnas.0937739100] [PMID: 12716974]
[38]
Grimm D, Lee JS, Wang L, et al. In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J Virol 2008; 82(12): 5887-911.
[http://dx.doi.org/10.1128/JVI.00254-08] [PMID: 18400866]
[39]
Koerber JT, Jang JH, Schaffer DV. DNA shuffling of adeno-associated virus yields functionally diverse viral progeny. Mol Ther 2008; 16(10): 1703-9.
[http://dx.doi.org/10.1038/mt.2008.167] [PMID: 18728640]
[40]
Li W, Asokan A, Wu Z, et al. Engineering and selection of shuffled AAV genomes: a new strategy for producing targeted biological nanoparticles. Mol Ther 2008; 16: 1252-60.
[http://dx.doi.org/10.1038/mt.2008.100]
[41]
Yang L, Jiang J, Drouin LM, et al. A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection. Proc Natl Acad Sci USA 2009; 106(10): 3946-51.
[http://dx.doi.org/10.1073/pnas.0813207106] [PMID: 19234115]
[42]
Li W, Zhang L, Johnson JS, et al. Generation of novel AAV variants by directed evolution for improved CFTR delivery to human ciliated airway epithelium. Mol Ther 2009; 17(12): 2067-77.
[http://dx.doi.org/10.1038/mt.2009.155] [PMID: 19603002]
[43]
Gray SJ, Blake BL, Criswell HE, et al. Directed evolution of a novel adeno-associated virus (AAV) vector that crosses the seizure-compromised blood-brain barrier (BBB). Mol Ther 2010; 18(3): 570-8.
[http://dx.doi.org/10.1038/mt.2009.292] [PMID: 20040913]
[44]
Lisowski L, Dane AP, Chu K, et al. Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature 2014; 506(7488): 382-6.
[http://dx.doi.org/10.1038/nature12875] [PMID: 24390344]
[45]
Choudhury SR, Fitzpatrick Z, Harris AF, et al. In vivo selection yields AAV-B1 capsid for central nervous system and muscle gene therapy. Mol Ther 2016; 24(7): 1247-57.
[http://dx.doi.org/10.1038/mt.2016.84] [PMID: 27117222]
[46]
Paulk NK, Pekrun K, Charville GW, et al. Bioengineered viral platform for intramuscular passive vaccine delivery to human skeletal muscle. Mol Ther Methods Clin Dev 2018; 10: 144-55.
[http://dx.doi.org/10.1016/j.omtm.2018.06.001] [PMID: 30101152]
[47]
Pekrun K, De Alencastro G, Luo Q-J, et al. Using a barcoded AAV capsid library to select for novel clinically relevant gene therapy vectors. bioRxiv 2019; 683672.
[http://dx.doi.org/10.1101/683672]
[48]
Müller OJ, Kaul F, Weitzman MD, et al. Random peptide libraries displayed on adeno-associated virus to select for targeted gene therapy vectors. Nat Biotechnol 2003; 21(9): 1040-6.
[http://dx.doi.org/10.1038/nbt856] [PMID: 12897791]
[49]
Perabo L, Büning H, Kofler DM, et al. In vitro selection of viral vectors with modified tropism: the adeno-associated virus display. Mol Ther 2003; 8(1): 151-7.
[http://dx.doi.org/10.1016/S1525-0016(03)00123-0] [PMID: 12842438]
[50]
Varadi K, Michelfelder S, Korff T, et al. Novel random peptide libraries displayed on AAV serotype 9 for selection of endothelial cell-directed gene transfer vectors. Gene Ther 2012; 19(8): 800-9.
[http://dx.doi.org/10.1038/gt.2011.143] [PMID: 21956692]
[51]
Koerber JT, Klimczak R, Jang JH, Dalkara D, Flannery JG, Schaffer DV. Molecular evolution of adeno-associated virus for enhanced glial gene delivery. Mol Ther 2009; 17(12): 2088-95.
[http://dx.doi.org/10.1038/mt.2009.184] [PMID: 19672246]
[52]
Marsic D, Govindasamy L, Currlin S, et al. Vector design Tour de Force: integrating combinatorial and rational approaches to derive novel adeno-associated virus variants. Mol Ther 2014; 22(11): 1900-9.
[http://dx.doi.org/10.1038/mt.2014.139] [PMID: 25048217]
[53]
Michelfelder S, Lee MK, deLima-Hahn E, et al. Vectors selected from adeno-associated viral display peptide libraries for leukemia cell-targeted cytotoxic gene therapy. Exp Hematol 2007; 35(12): 1766-76.
[http://dx.doi.org/10.1016/j.exphem.2007.07.018] [PMID: 17920758]
[54]
Sellner L, Stiefelhagen M, Kleinschmidt JA, et al. Generation of efficient human blood progenitor-targeted recombinant adeno-associated viral vectors (AAV) by applying an AAV random peptide library on primary human hematopoietic progenitor cells. Exp Hematol 2008; 36(8): 957-64.
[http://dx.doi.org/10.1016/j.exphem.2008.03.007] [PMID: 18495326]
[55]
Zhang L, Rossi A, Lange L, et al. Capsid engineering overcomes barriers toward adeno-associated virus vector-mediated transduction of endothelial cells. Hum Gene Ther 2019; 30(10): 1284-96.
[http://dx.doi.org/10.1089/hum.2019.027] [PMID: 31407607]
[56]
Jang JH, Koerber JT, Kim JS, et al. An evolved adeno-associated viral variant enhances gene delivery and gene targeting in neural stem cells. Mol Ther 2011; 19(4): 667-75.
[http://dx.doi.org/10.1038/mt.2010.287] [PMID: 21224831]
[57]
Dalkara D, Byrne LC, Klimczak RR, et al. In vivo -directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous. Sci Transl Med 2013; 5(189): 189ra76.
[http://dx.doi.org/10.1126/scitranslmed.3005708] [PMID: 23761039]
[58]
Tervo DGR, Hwang BY, Viswanathan S, et al. A designer AAV variant permits efficient retrograde access to projection neurons. Neuron 2016; 92(2): 372-82.
[http://dx.doi.org/10.1016/j.neuron.2016.09.021] [PMID: 27720486]
[59]
Körbelin J, Dogbevia G, Michelfelder S, et al. A brain microvasculature endothelial cell-specific viral vector with the potential to treat neurovascular and neurological diseases. EMBO Mol Med 2016; 8(6): 609-25.
[http://dx.doi.org/10.15252/emmm.201506078] [PMID: 27137490]
[60]
Deverman BE, Pravdo PL, Simpson BP, et al. Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat Biotechnol 2016; 34(2): 204-9.
[http://dx.doi.org/10.1038/nbt.3440] [PMID: 26829320]
[61]
Matsuzaki Y, Konno A, Mochizuki R, et al. Intravenous administration of the adeno-associated virus-PHP.B capsid fails to upregulate transduction efficiency in the marmoset brain. Neurosci Lett 2018; 665: 182-8.
[http://dx.doi.org/10.1016/j.neulet.2017.11.049] [PMID: 29175632]
[62]
Hordeaux J, Wang Q, Katz N, Buza EL, Bell P, Wilson JM. The neurotropic properties of AAV-PHP. B are limited to C57BL/6J mice. Mol Ther 2018; 26(3): 664-8.
[http://dx.doi.org/10.1016/j.ymthe.2018.01.018] [PMID: 29428298]
[63]
Paulk NK, Pekrun K, Zhu E, et al. Bioengineered AAV capsids with combined high human liver transduction in vivo and unique humoral seroreactivity. Mol Ther 2018; 26(1): 289-303.
[http://dx.doi.org/10.1016/j.ymthe.2017.09.021] [PMID: 29055620]
[64]
Byrne LC, Day TP, Visel M, et al. In vivo directed evolution of AAV in the primate retina. bioRxiv 2019; 847459.
[http://dx.doi.org/10.1172/jci.insight.135112] [PMID: 32271719]
[65]
Zinn E, Pacouret S, Khaychuk V, et al. In silico reconstruction of the viral evolutionary lineage yields a potent gene therapy vector. Cell Rep 2015; 12(6): 1056-68.
[http://dx.doi.org/10.1016/j.celrep.2015.07.019] [PMID: 26235624]
[66]
Landegger LD, Pan B, Askew C, et al. A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear. Nat Biotechnol 2017; 35(3): 280-4.
[http://dx.doi.org/10.1038/nbt.3781] [PMID: 28165475]
[67]
Pan B, Askew C, Galvin A, et al. Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c. Nat Biotechnol 2017; 35(3): 264-72.
[http://dx.doi.org/10.1038/nbt.3801] [PMID: 28165476]
[68]
Santiago-Ortiz J, Ojala DS, Westesson O, et al. AAV ancestral reconstruction library enables selection of broadly infectious viral variants. Gene Ther 2015; 22(12): 934-46.
[http://dx.doi.org/10.1038/gt.2015.74] [PMID: 26186661]
[69]
Ho ML, Adler BA, Torre ML, Silberg JJ, Suh J. SCHEMA computational design of virus capsid chimeras: calibrating how genome packaging, protection, and transduction correlate with calculated structural disruption. ACS Synth Biol 2013; 2(12): 724-33.
[http://dx.doi.org/10.1021/sb400076r] [PMID: 23899192]
[70]
Ojala DS, Sun S, Santiago-Ortiz JL, Shapiro MG, Romero PA, Schaffer DV. In vivo selection of a computationally designed SCHEMA AAV library yields a novel variant for infection of adult neural stem cells in the SVZ. Mol Ther 2018; 26(1): 304-19.
[http://dx.doi.org/10.1016/j.ymthe.2017.09.006] [PMID: 28988711]
[71]
Ogden PJ, Kelsic ED, Sinai S, Church GM. Comprehensive AAV capsid fitness landscape reveals a viral gene and enables machine-guided design. Science 2019; 366(6469): 1139-43.
[http://dx.doi.org/10.1126/science.aaw2900] [PMID: 31780559]
[72]
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. Nat Med 2006; 12(3): 342-7.
[http://dx.doi.org/10.1038/nm1358] [PMID: 16474400]
[73]
Nathwani AC, Tuddenham EGD, Rangarajan S, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 2011; 365(25): 2357-65.
[http://dx.doi.org/10.1056/NEJMoa1108046] [PMID: 22149959]
[74]
Boutin S, Monteilhet V, Veron P, et al. Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors. Hum Gene Ther 2010; 21(6): 704-12.
[http://dx.doi.org/10.1089/hum.2009.182] [PMID: 20095819]
[75]
Lochrie MA, Tatsuno GP, Christie B, et al. Mutations on the external surfaces of adeno-associated virus type 2 capsids that affect transduction and neutralization. J Virol 2006; 80(2): 821-34.
[http://dx.doi.org/10.1128/JVI.80.2.821-834.2006] [PMID: 16378984]
[76]
Giles AR, Govindasamy L, Somanathan S, Wilson JM. Mapping an adeno-associated virus 9-specific neutralizing epitope to develop next-generation gene delivery vectors. J Virol 2018; 92(20): e01011-8.
[http://dx.doi.org/10.1128/JVI.01011-18] [PMID: 30089698]
[77]
Maersch S, Huber A, Büning H, Hallek M, Perabo L. Optimization of stealth adeno-associated virus vectors by randomization of immunogenic epitopes. Virology 2010; 397(1): 167-75.
[http://dx.doi.org/10.1016/j.virol.2009.10.021] [PMID: 19926109]
[78]
Tse LV, Klinc KA, Madigan VJ, et al. Structure-guided evolution of antigenically distinct adeno-associated virus variants for immune evasion. Proc Natl Acad Sci USA 2017; 114(24): E4812-21.
[http://dx.doi.org/10.1073/pnas.1704766114] [PMID: 28559317]
[79]
Ponnazhagan S, Weigel KA, Raikwar SP, Mukherjee P, Yoder MC, Srivastava A. Recombinant human parvovirus B19 vectors: erythroid cell-specific delivery and expression of transduced genes. J Virol 1998; 72(6): 5224-30.
[http://dx.doi.org/10.1128/JVI.72.6.5224-5230.1998] [PMID: 9573295]
[80]
Yan Z, Keiser NW, Song Y, et al. A novel chimeric adenoassociated virus 2/human bocavirus 1 parvovirus vector efficiently transduces human airway epithelia. Mol Ther 2013; 21(12): 2181-94.
[http://dx.doi.org/10.1038/mt.2013.92] [PMID: 23896725]
[81]
Fakhiri J, Schneider MA, Puschhof J, et al. Novel chimeric gene therapy vectors based on Adeno-Associated virus and four different mammalian bocaviruses. Mol Ther Methods Clin Dev 2019; 12: 202-22.
[http://dx.doi.org/10.1016/j.omtm.2019.01.003] [PMID: 30766894]

Rights & Permissions Print Cite
Article Metrics
60
1
© 2024 Bentham Science Publishers | Privacy Policy