Gene Therapy for Hemophilia A: Where We Stand

Author(s): Miaojin Zhou, Zhiqing Hu, Chunhua Zhang, Lingqian Wu, Zhuo Li*, Desheng Liang*

Journal Name: Current Gene Therapy

Volume 20 , Issue 2 , 2020


  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Hemophilia A (HA) is a hereditary hemorrhagic disease caused by a deficiency of coagulation factor VIII (FVIII) in blood plasma. Patients with HA usually suffer from spontaneous and recurrent bleeding in joints and muscles, or even intracerebral hemorrhage, which might lead to disability or death. Although the disease is currently manageable via delivery of plasma-derived or recombinant FVIII, this approach is costly, and neutralizing antibodies may be generated in a large portion of patients, which render the regimens ineffective and inaccessible. Given the monogenic nature of HA and that a slight increase in FVIII can remarkably alleviate the phenotypes, HA has been considered to be a suitable target disease for gene therapy. Consequently, the introduction of a functional F8 gene copy into the appropriate target cells via viral or nonviral delivery vectors, including gene correction through genome editing approaches, could ultimately provide an effective therapeutic method for HA patients. In this review, we discuss the recent progress of gene therapy for HA with viral and nonviral delivery vectors, including piggyBac, lentiviral and adeno-associated viral vectors, as well as new raising issues involving liver toxicity, pre-existing neutralizing antibodies of viral approach, and the selection of the target cell type for nonviral delivery.

Keywords: Hemophilia A, gene therapy, BDD-F8, lentiviral, adeno-associated viral, nonviral.

[1]
Hedner U, Ginsburg D, Lusher JM, High KA. Congenital Hemorrhagic Disorders: New Insights into the Pathophysiology and Treatment of Hemophilia. Hematology (Am Soc Hematol Educ Program) 2000; 241-65.
[http://dx.doi.org/10.1182/asheducation.V2000.1.241.241] [PMID: 11701545]
[2]
Pipe SW, High KA, Ohashi K, Ural AU, Lillicrap D. Progress in the molecular biology of inherited bleeding disorders. Haemophilia 2008; 14(Suppl. 3): 130-7.
[http://dx.doi.org/10.1111/j.1365-2516.2008.01718.x] [PMID: 18510533]
[3]
Boardman FK, Hale R, Young PJ. Newborn screening for haemophilia: The views of families and adults living with haemophilia in the UK. Haemophilia 2019; 25(2): 276-82.
[http://dx.doi.org/10.1111/hae.13706] [PMID: 30817064]
[4]
Graw J, Brackmann HH, Oldenburg J, Schneppenheim R, Spannagl M, Schwaab R. Haemophilia A: from mutation analysis to new therapies. Nat Rev Genet 2005; 6(6): 488-501.
[http://dx.doi.org/10.1038/nrg1617] [PMID: 15931172]
[5]
Pierce GF, Lillicrap D, Pipe SW, Vandendriessche T. Gene therapy, bioengineered clotting factors and novel technologies for hemophilia treatment. J Thromb Haemost 2007; 5(5): 901-6.
[http://dx.doi.org/10.1111/j.1538-7836.2007.02410.x] [PMID: 17459005]
[6]
Franchini M, Marano G, Pati I, et al. Emicizumab for the treatment of haemophilia A: a narrative review. Blood Transfus 2019; 17(3): 223-8.
[PMID: 31246563]
[7]
Russick J, Delignat S, Milanov P, et al. Correction of bleeding in experimental severe hemophilia A by systemic delivery of factor VIII-encoding mRNA. Haematologica 2020; 105(4): 1129-37.
[http://dx.doi.org/10.3324/haematol.2018.210583] [PMID: 31289204]
[8]
Soucie JM, Monahan PE, Kulkarni R, Konkle BA, Mazepa MA. The frequency of joint hemorrhages and procedures in nonsevere hemophilia A vs B. Blood Adv 2018; 2(16): 2136-44.
[http://dx.doi.org/10.1182/bloodadvances.2018020552] [PMID: 30143528]
[9]
Saint-Remy JM, Lacroix-Desmazes S, Oldenburg J. Inhibitors in haemophilia: pathophysiology. Haemophilia 2004; 10(Suppl. 4): 146-51.
[http://dx.doi.org/10.1111/j.1365-2516.2004.01009.x] [PMID: 15479388]
[10]
Peyvandi F, Mannucci PM, Garagiola I, et al. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med 2016; 374(21): 2054-64.
[http://dx.doi.org/10.1056/NEJMoa1516437] [PMID: 27223147]
[11]
Steinman L, Ho PP, Robinson WH, Utz PJ, Villoslada P. Antigen-specific tolerance to self-antigens in protein replacement therapy, gene therapy and autoimmunity. Curr Opin Immunol 2019; 61: 46-53.
[http://dx.doi.org/10.1016/j.coi.2019.07.011] [PMID: 31476445]
[12]
Nathwani AC, Davidoff AM, Tuddenham EG. Prospects for gene therapy of haemophilia. Haemophilia 2004; 10(4): 309-18.
[http://dx.doi.org/10.1111/j.1365-2516.2004.00926.x] [PMID: 15230943]
[13]
VandenDriessche T, Collen D, Chuah MK. Gene therapy for the hemophilias. J Thromb Haemost 2003; 1(7): 1550-8.
[http://dx.doi.org/10.1046/j.1538-7836.2003.00265.x] [PMID: 12871290]
[14]
Guo XL, Chung TH, Qin Y, et al. Hemophilia gene therapy: new development from bench to bed side. Curr Gene Ther 2019; 19(4): 264-73.
[http://dx.doi.org/10.2174/1566523219666190924121836] [PMID: 31549954]
[15]
White M, Whittaker R, Gándara C, Stoll EA. A Guide to approaching regulatory considerations for lentiviral-mediated gene therapies. Hum Gene Ther Methods 2017; 28(4): 163-76.
[http://dx.doi.org/10.1089/hgtb.2017.096] [PMID: 28817344]
[16]
Rothe M, Modlich U, Schambach A. Biosafety challenges for use of lentiviral vectors in gene therapy. Curr Gene Ther 2013; 13(6): 453-68.
[http://dx.doi.org/10.2174/15665232113136660006] [PMID: 24195603]
[17]
Wang W, Fasolino M, Cattau B, et al. Joint profiling of chromatin accessibility and CAR-T integration site analysis at population and single-cell levels. Proc Natl Acad Sci USA 2020; 117(10): 5442-52.
[http://dx.doi.org/10.1073/pnas.1919259117] [PMID: 32094195]
[18]
Anthony-Gonda K, Bardhi A, Ray A, et al. Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model. Sci Transl Med 2019; 11(504) eaav5685
[http://dx.doi.org/10.1126/scitranslmed.aav5685] [PMID: 31391322]
[19]
Takushi SE, Paik NY, Fedanov A, et al. Lentiviral gene therapy for familial hemophagocytic lymphohistiocytosis type 3, caused by UNC13D genetic defects. Hum Gene Ther 2020; 31(11-12): 626-38.
[http://dx.doi.org/10.1089/hum.2019.329] [PMID: 32253931]
[20]
van den Biggelaar M, Bierings R, Storm G, Voorberg J, Mertens K. Requirements for cellular co-trafficking of factor VIII and von Willebrand factor to Weibel-Palade bodies. J Thromb Haemost 2007; 5(11): 2235-42.
[http://dx.doi.org/10.1111/j.1538-7836.2007.02737.x] [PMID: 17958741]
[21]
Gao K, Kumar P, Cortez-Toledo E, et al. Potential long-term treatment of hemophilia A by neonatal co-transplantation of cord blood-derived endothelial colony-forming cells and placental mesenchymal stromal cells. Stem Cell Res Ther 2019; 10(1): 34.
[http://dx.doi.org/10.1186/s13287-019-1138-8] [PMID: 30670078]
[22]
Ozelo MC, Vidal B, Brown C, et al. Omental implantation of BOECs in hemophilia dogs results in circulating FVIII antigen and a complex immune response. Blood 2014; 123(26): 4045-53.
[http://dx.doi.org/10.1182/blood-2013-12-545780] [PMID: 24829206]
[23]
Olgasi C, Talmon M, Merlin S, et al. Patient-Specific iPSC-derived endothelial cells provide long-term phenotypic correction of hemophilia A. Stem Cell Reports 2018; 11(6): 1391-406.
[http://dx.doi.org/10.1016/j.stemcr.2018.10.012] [PMID: 30416049]
[24]
Rose M, Gao K, Cortez-Toledo E, et al. Endothelial cells derived from patients’ induced pluripotent stem cells for sustained factor VIII delivery and the treatment of hemophilia A. Stem Cells Transl Med 2020; 9(6): 686-96.
[http://dx.doi.org/10.1002/sctm.19-0261] [PMID: 32162786]
[25]
Porada CD, Sanada C, Kuo CJ, et al. Phenotypic correction of hemophilia A in sheep by postnatal intraperitoneal transplantation of FVIII-expressing MSC. Exp Hematol 2011; 39(12): 1124-35.
[26]
Tie R, Li H, Cai S, et al. Interleukin-6 signaling regulates hematopoietic stem cell emergence. Exp Mol Med 2019; 51(10): 1-12.
[http://dx.doi.org/10.1038/s12276-019-0320-5] [PMID: 31649245]
[27]
Doering CB, Denning G, Shields JE, et al. Preclinical development of a hematopoietic stem and progenitor cell bioengineered factor VIII lentiviral vector gene therapy for hemophilia A. Hum Gene Ther 2018; 29(10): 1183-201.
[http://dx.doi.org/10.1089/hum.2018.137] [PMID: 30160169]
[28]
Du LM, Nurden P, Nurden AT, et al. Platelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A. Nat Commun 2013; 4: 2773.
[http://dx.doi.org/10.1038/ncomms3773] [PMID: 24253479]
[29]
Montgomery RR, Shi Q. Platelet and endothelial expression of clotting factors for the treatment of hemophilia. Thromb Res 2012; 129(Suppl. 2): S46-8.
[http://dx.doi.org/10.1016/j.thromres.2012.02.031] [PMID: 22421106]
[30]
Shi Q, Wilcox DA, Fahs SA, et al. Lentivirus-mediated platelet-derived factor VIII gene therapy in murine haemophilia A. J Thromb Haemost 2007; 5(2): 352-61.
[http://dx.doi.org/10.1111/j.1538-7836.2007.02346.x] [PMID: 17269937]
[31]
Doering CB, Denning G, Dooriss K, et al. Directed engineering of a high-expression chimeric transgene as a strategy for gene therapy of hemophilia A. Mol Ther 2009; 17(7): 1145-54.
[http://dx.doi.org/10.1038/mt.2009.35] [PMID: 19259064]
[32]
Gao C, Schroeder JA, Xue F, et al. Nongenotoxic antibody-drug conjugate conditioning enables safe and effective platelet gene therapy of hemophilia A mice. Blood Adv 2019; 3(18): 2700-11.
[http://dx.doi.org/10.1182/bloodadvances.2019000516] [PMID: 31515232]
[33]
Schroeder JA, Chen Y, Fang J, Wilcox DA, Shi Q. In vivo enrichment of genetically manipulated platelets corrects the murine hemophilic phenotype and induces immune tolerance even using a low multiplicity of infection. J Thromb Haemost 2014; 12(8): 1283-93.
[http://dx.doi.org/10.1111/jth.12633] [PMID: 24931217]
[34]
Shi Q, Kuether EL, Chen Y, Schroeder JA, Fahs SA, Montgomery RR. Platelet gene therapy corrects the hemophilic phenotype in immunocompromised hemophilia A mice transplanted with genetically manipulated human cord blood stem cells. Blood 2014; 123(3): 395-403.
[http://dx.doi.org/10.1182/blood-2013-08-520478] [PMID: 24269957]
[35]
Ramezani A, Zweier-Renn LA, Hawley RG. Factor VIII delivered by haematopoietic stem cell-derived B cells corrects the phenotype of haemophilia A mice. Thromb Haemost 2011; 105(4): 676-87.
[http://dx.doi.org/10.1160/TH10-11-0725] [PMID: 21264447]
[36]
Kuether EL, Schroeder JA, Fahs SA, et al. Lentivirus-mediated platelet gene therapy of murine hemophilia A with pre-existing anti-factor VIII immunity. J Thromb Haemost 2012; 10(8): 1570-80.
[http://dx.doi.org/10.1111/j.1538-7836.2012.04791.x] [PMID: 22632092]
[37]
Shi Q, Schroeder JA, Kuether EL, Montgomery RR. The important role of von Willebrand factor in platelet-derived FVIII gene therapy for murine hemophilia A in the presence of inhibitory antibodies. J Thromb Haemost 2015; 13(7): 1301-9.
[http://dx.doi.org/10.1111/jth.13001] [PMID: 25955153]
[38]
Chen Y, Luo X, Schroeder JA, et al. Immune tolerance induced by platelet-targeted factor VIII gene therapy in hemophilia A mice is CD4 T cell mediated. J Thromb Haemost 2017; 15(10): 1994-2004.
[http://dx.doi.org/10.1111/jth.13800] [PMID: 28799202]
[39]
Wang X, Shin SC, Chiang AF, et al. Intraosseous delivery of lentiviral vectors targeting factor VIII expression in platelets corrects murine hemophilia A. Mol Ther 2015; 23(4): 617-26.
[http://dx.doi.org/10.1038/mt.2015.20] [PMID: 25655313]
[40]
Staber JM, Pollpeter MJ, Anderson CG, et al. Long-term correction of hemophilia A mice following lentiviral mediated delivery of an optimized canine factor VIII gene. Gene Ther 2017; 24(11): 742-8.
[http://dx.doi.org/10.1038/gt.2017.67] [PMID: 28905885]
[41]
Merlin S, Famà R, Borroni E, et al. FVIII expression by its native promoter sustains long-term correction avoiding immune response in hemophilic mice. Blood Adv 2019; 3(5): 825-38.
[http://dx.doi.org/10.1182/bloodadvances.2018027979] [PMID: 30862611]
[42]
VandenDriessche T, Thorrez L, Naldini L, et al. Lentiviral vectors containing the human immunodeficiency virus type-1 central polypurine tract can efficiently transduce nondividing hepatocytes and antigen-presenting cells in vivo. Blood 2002; 100(3): 813-22.
[http://dx.doi.org/10.1182/blood.V100.3.813] [PMID: 12130491]
[43]
Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature 2010; 467(7313): 318-22.
[http://dx.doi.org/10.1038/nature09328] [PMID: 20844535]
[44]
Lukashev AN, Zamyatnin AA Jr. Viral Vectors for gene therapy: current state and clinical perspectives. Biochemistry (Mosc) 2016; 81(7): 700-8.
[http://dx.doi.org/10.1134/S0006297916070063] [PMID: 27449616]
[45]
VandenDriessche T, Chuah MK. Hemophilia gene therapy: ready for prime time? Hum Gene Ther 2017; 28(11): 1013-23.
[http://dx.doi.org/10.1089/hum.2017.116] [PMID: 28793786]
[46]
Perrin GQ, Herzog RW, Markusic DM. Update on clinical gene therapy for hemophilia. Blood 2019; 133(5): 407-14.
[http://dx.doi.org/10.1182/blood-2018-07-820720] [PMID: 30559260]
[47]
Atchison RW, Casto BC, Hammon WM. Adenovirus-associated defective virus particles. Science 1965; 149(3685): 754-6.
[http://dx.doi.org/10.1126/science.149.3685.754] [PMID: 14325163]
[48]
Mingozzi F, High KA. Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges. Nat Rev Genet 2011; 12(5): 341-55.
[http://dx.doi.org/10.1038/nrg2988] [PMID: 21499295]
[49]
Kattenhorn LM, Tipper CH, Stoica L, et al. Adeno-associated virus gene therapy for liver disease. Hum Gene Ther 2016; 27(12): 947-61.
[http://dx.doi.org/10.1089/hum.2016.160] [PMID: 27897038]
[50]
Nathwani AC, Tuddenham EG, 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]
[51]
Nathwani AC, Reiss UM, Tuddenham EG, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 2014; 371(21): 1994-2004.
[http://dx.doi.org/10.1056/NEJMoa1407309] [PMID: 25409372]
[52]
Sarkar R, Tetreault R, Gao G, et al. Total correction of hemophilia A mice with canine FVIII using an AAV 8 serotype. Blood 2004; 103(4): 1253-60.
[http://dx.doi.org/10.1182/blood-2003-08-2954] [PMID: 14551134]
[53]
Sabatino DE, Lange AM, Altynova ES, et al. Efficacy and safety of long-term prophylaxis in severe hemophilia A dogs following liver gene therapy using AAV vectors. Mol Ther 2011; 19(3): 442-9.
[http://dx.doi.org/10.1038/mt.2010.240] [PMID: 21081906]
[54]
Gao G, Vandenberghe LH, Alvira MR, et al. Clades of Adeno-associated viruses are widely disseminated in human tissues. J Virol 2004; 78(12): 6381-8.
[http://dx.doi.org/10.1128/JVI.78.12.6381-6388.2004] [PMID: 15163731]
[55]
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]
[56]
Vercauteren K, Hoffman BE, Zolotukhin I, et al. Superior in vivo transduction of human hepatocytes using engineered AAV3 capsid. Mol Ther 2016; 24(6): 1042-9.
[http://dx.doi.org/10.1038/mt.2016.61] [PMID: 27019999]
[57]
McIntosh J, Lenting PJ, Rosales C, et al. Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant. Blood 2013; 121(17): 3335-44.
[http://dx.doi.org/10.1182/blood-2012-10-462200] [PMID: 23426947]
[58]
Siner JI, Iacobelli NP, Sabatino DE, et al. Minimal modification in the factor VIII B-domain sequence ameliorates the murine hemophilia A phenotype. Blood 2013; 121(21): 4396-403.
[http://dx.doi.org/10.1182/blood-2012-10-464164] [PMID: 23372167]
[59]
Nguyen GN, George LA, Siner JI, et al. Novel factor VIII variants with a modified furin cleavage site improve the efficacy of gene therapy for hemophilia A. J Thromb Haemost 2017; 15(1): 110-21.
[http://dx.doi.org/10.1111/jth.13543] [PMID: 27749002]
[60]
Brown HC, Wright JF, Zhou S, et al. Bioengineered coagulation factor VIII enables long-term correction of murine hemophilia A following liver-directed adeno-associated viral vector delivery. Mol Ther Methods Clin Dev 2014; 1: 14036.
[http://dx.doi.org/10.1038/mtm.2014.36] [PMID: 26015976]
[61]
Greig JA, Wang Q, Reicherter AL, et al. Characterization of adeno-associated viral vector-mediated human factor VIII gene therapy in hemophilia A mice. Hum Gene Ther 2017; 28(5): 392-402.
[http://dx.doi.org/10.1089/hum.2016.128] [PMID: 28056565]
[62]
Siner JI, Samelson-Jones BJ, Crudele JM, et al. Circumventing furin enhances factor VIII biological activity and ameliorates bleeding phenotypes in hemophilia models. JCI Insight 2016; 1(16) e89371
[http://dx.doi.org/10.1172/jci.insight.89371] [PMID: 27734034]
[63]
Brown HC, Zakas PM, George SN, Parker ET, Spencer HT, Doering CB. Target-cell-directed bioengineering approaches for gene therapy of hemophilia A. Mol Ther Methods Clin Dev 2018; 9: 57-69.
[http://dx.doi.org/10.1016/j.omtm.2018.01.004] [PMID: 29552578]
[64]
Sharma R, Anguela XM, Doyon Y, et al. In vivo genome editing of the albumin locus as a platform for protein replacement therapy. Blood 2015; 126(15): 1777-84.
[http://dx.doi.org/10.1182/blood-2014-12-615492] [PMID: 26297739]
[65]
Zhang JP, Cheng XX, Zhao M, et al. Curing hemophilia A by NHEJ-mediated ectopic F8 insertion in the mouse. Genome Biol 2019; 20(1): 276.
[http://dx.doi.org/10.1186/s13059-019-1907-9] [PMID: 31843008]
[66]
Bunting S, Zhang L, Xie L, et al. Gene therapy with BMN 270 results in therapeutic levels of FVIII in mice and primates and normalization of bleeding in hemophilic mice. Mol Ther 2018; 26(2): 496-509.
[http://dx.doi.org/10.1016/j.ymthe.2017.12.009] [PMID: 29292164]
[67]
Rangarajan S, Walsh L, Lester W, et al. AAV5-Factor VIII gene transfer in severe hemophilia A. N Engl J Med 2017; 377(26): 2519-30.
[http://dx.doi.org/10.1056/NEJMoa1708483] [PMID: 29224506]
[68]
Pasi KJ, Rangarajan S, Mitchell N, et al. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N Engl J Med 2020; 382(1): 29-40.
[http://dx.doi.org/10.1056/NEJMoa1908490] [PMID: 31893514]
[69]
Shestopal SA, Hao JJ, Karnaukhova E, et al. Expression and characterization of a codon-optimized blood coagulation factor VIII. J Thromb Haemost 2017; 15(4): 709-20.
[http://dx.doi.org/10.1111/jth.13632] [PMID: 28109042]
[70]
Colella P, Ronzitti G, Mingozzi F. Emerging issues in aav-mediated in vivo gene therapy. Mol Ther Methods Clin Dev 2017; 8: 87-104.
[http://dx.doi.org/10.1016/j.omtm.2017.11.007] [PMID: 29326962]
[71]
Negrete A, Yang LC, Mendez AF, Levy JR, Kotin RM. Economized large-scale production of high yield of rAAV for gene therapy applications exploiting baculovirus expression system. J Gene Med 2007; 9(11): 938-48.
[http://dx.doi.org/10.1002/jgm.1092] [PMID: 17764098]
[72]
Kondratov O, Marsic D, Crosson SM, et al. Direct head-to-head evaluation of recombinant adeno-associated viral vectors manufactured in human versus insect cells. Mol Ther 2017; 25(12): 2661-75.
[http://dx.doi.org/10.1016/j.ymthe.2017.08.003] [PMID: 28890324]
[73]
Nambiar B, Cornell Sookdeo C, Berthelette P, et al. Characteristics of minimally oversized adeno-associated virus vectors encoding human factor VIII generated using producer cell lines and triple transfection. Hum Gene Ther Methods 2017; 28(1): 23-38.
[http://dx.doi.org/10.1089/hgtb.2016.124] [PMID: 28166648]
[74]
Donsante A, Miller DG, Li Y, et al. AAV vector integration sites in mouse hepatocellular carcinoma. Science 2007; 317(5837): 477.
[http://dx.doi.org/10.1126/science.1142658] [PMID: 17656716]
[75]
Nault JC, Datta S, Imbeaud S, et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet 2015; 47(10): 1187-93.
[http://dx.doi.org/10.1038/ng.3389] [PMID: 26301494]
[76]
Nault JC, Mami I, La Bella T, et al. Wild-type AAV insertions in hepatocellular carcinoma do not inform debate over genotoxicity risk of vectorized AAV. Mol Ther 2016; 24(4): 660-1.
[http://dx.doi.org/10.1038/mt.2016.47] [PMID: 27081717]
[77]
Chandler RJ, LaFave MC, Varshney GK, et al. Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J Clin Invest 2015; 125(2): 870-80.
[http://dx.doi.org/10.1172/JCI79213] [PMID: 25607839]
[78]
Ertl HCJ, High KA. Impact of AAV Capsid-specific T-cell responses on design and outcome of clinical gene transfer trials with recombinant adeno-associated viral vectors: an evolving controversy. Hum Gene Ther 2017; 28(4): 328-37.
[http://dx.doi.org/10.1089/hum.2016.172] [PMID: 28042943]
[79]
Calcedo R, Morizono H, Wang L, et al. Adeno-associated virus antibody profiles in newborns, children, and adolescents. Clin Vaccine Immunol 2011; 18(9): 1586-8.
[http://dx.doi.org/10.1128/CVI.05107-11] [PMID: 21775517]
[80]
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]
[81]
Long BR, Sandza K, Holcomb J, et al. The impact of pre-existing immunity on the non-clinical pharmacodynamics of aav5-based gene therapy. Mol Ther Methods Clin Dev 2019; 13: 440-52.
[http://dx.doi.org/10.1016/j.omtm.2019.03.006] [PMID: 31193016]
[82]
Sun J, Shao W, Chen X, et al. An observational study from long-term aav re-administration in two hemophilia dogs. Mol Ther Methods Clin Dev 2018; 10: 257-67.
[http://dx.doi.org/10.1016/j.omtm.2018.07.011] [PMID: 30140713]
[83]
Hu C, Lipshutz GS. AAV-based neonatal gene therapy for hemophilia A: long-term correction and avoidance of immune responses in mice. Gene Ther 2012; 19(12): 1166-76.
[http://dx.doi.org/10.1038/gt.2011.200] [PMID: 22241178]
[84]
Lange AM, Altynova ES, Nguyen GN, Sabatino DE. Overexpression of factor VIII after AAV delivery is transiently associated with cellular stress in hemophilia A mice. Mol Ther Methods Clin Dev 2016; 3: 16064.
[http://dx.doi.org/10.1038/mtm.2016.64] [PMID: 27738645]
[85]
Zolotukhin I, Markusic DM, Palaschak B, Hoffman BE, Srikanthan MA, Herzog RW. Potential for cellular stress response to hepatic factor VIII expression from AAV vector. Mol Ther Methods Clin Dev 2016; 3: 16063.
[http://dx.doi.org/10.1038/mtm.2016.63] [PMID: 27738644]
[86]
Bantel-Schaal U. Infection with adeno-associated parvovirus leads to increased sensitivity of mammalian cells to stress. Virology 1991; 182(1): 260-8.
[http://dx.doi.org/10.1016/0042-6822(91)90669-3] [PMID: 1850906]
[87]
Schwartz RA, Carson CT, Schuberth C, Weitzman MD. Adeno-associated virus replication induces a DNA damage response coordinated by DNA-dependent protein kinase. J Virol 2009; 83(12): 6269-78.
[http://dx.doi.org/10.1128/JVI.00318-09] [PMID: 19339345]
[88]
Hirsch ML, Fagan BM, Dumitru R, et al. Viral single-strand DNA induces p53-dependent apoptosis in human embryonic stem cells. PLoS One 2011; 6(11) e27520
[http://dx.doi.org/10.1371/journal.pone.0027520] [PMID: 22114676]
[89]
Johnson JS, Gentzsch M, Zhang L, et al. AAV exploits subcellular stress associated with inflammation, endoplasmic reticulum expansion, and misfolded proteins in models of cystic fibrosis. PLoS Pathog 2011; 7(5) e1002053
[http://dx.doi.org/10.1371/journal.ppat.1002053] [PMID: 21625534]
[90]
Mitchell AM, Li C, Samulski RJ. Arsenic trioxide stabilizes accumulations of adeno-associated virus virions at the perinuclear region, increasing transduction in vitro and in vivo. J Virol 2013; 87(8): 4571-83.
[http://dx.doi.org/10.1128/JVI.03443-12] [PMID: 23408604]
[91]
Park CY, Kim J, Kweon J, et al. Targeted inversion and reversion of the blood coagulation factor 8 gene in human iPS cells using TALENs. Proc Natl Acad Sci USA 2014; 111(25): 9253-8.
[http://dx.doi.org/10.1073/pnas.1323941111] [PMID: 24927536]
[92]
Park CY, Kim DH, Son JS, et al. Functional correction of large factor VIII gene chromosomal inversions in hemophilia a patient-derived iPSCs using CRISPR-Cas9. Cell Stem Cell 2015; 17(2): 213-20.
[http://dx.doi.org/10.1016/j.stem.2015.07.001] [PMID: 26212079]
[93]
Wu Y, Hu Z, Li Z, et al. In situ genetic correction of F8 intron 22 inversion in hemophilia A patient-specific iPSCs. Sci Rep 2016; 6: 18865.
[http://dx.doi.org/10.1038/srep18865] [PMID: 26743572]
[94]
Hu Z, Zhou M, Wu Y, et al. ssODN-mediated in-frame deletion with CRISPR/Cas9 restores FVIII function in hemophilia A-patient-derived iPSCs and ECs. Mol Ther Nucleic Acids 2019; 17: 198-209.
[http://dx.doi.org/10.1016/j.omtn.2019.05.019] [PMID: 31261034]
[95]
Choi JG, Dang Y, Abraham S, et al. Lentivirus pre-packed with Cas9 protein for safer gene editing. Gene Ther 2016; 23(7): 627-33.
[http://dx.doi.org/10.1038/gt.2016.27] [PMID: 27052803]
[96]
Sivalingam J, Kenanov D, Han H, et al. Multidimensional genome-wide analyses show accurate FVIII integration by ZFN in primary human cells. Mol Ther 2016; 24(3): 607-19.
[http://dx.doi.org/10.1038/mt.2015.223] [PMID: 26689265]
[97]
Park CY, Sung JJ, Cho SR, Kim J, Kim DW. Universal correction of blood coagulation factor VIII in patient-derived induced pluripotent stem cells using CRISPR/Cas9. Stem Cell Reports 2019; 12(6): 1242-9.
[http://dx.doi.org/10.1016/j.stemcr.2019.04.016] [PMID: 31105049]
[98]
Ponomartsev SV, Sinenko SA, Skvortsova EV, et al. Human alphoidtetO artificial chromosome as a gene therapy vector for the developing hemophilia a model in mice. Cells 2020; 9(4) E879
[http://dx.doi.org/10.3390/cells9040879] [PMID: 32260189]
[99]
Yakura Y, Ishihara C, Kurosaki H, et al. An induced pluripotent stem cell-mediated and integration-free factor VIII expression system. Biochem Biophys Res Commun 2013; 431(2): 336-41.
[http://dx.doi.org/10.1016/j.bbrc.2012.12.096] [PMID: 23291180]
[100]
Pang J, Wu Y, Li Z, et al. Targeting of the human F8 at the multicopy rDNA locus in Hemophilia A patient-derived iPSCs using TALENickases. Biochem Biophys Res Commun 2016; 472(1): 144-9.
[http://dx.doi.org/10.1016/j.bbrc.2016.02.083] [PMID: 26921444]
[101]
Neumeyer J, Lin RZ, Wang K, et al. Bioengineering hemophilia A-specific microvascular grafts for delivery of full-length factor VIII into the bloodstream. Blood Adv 2019; 3(24): 4166-76.
[http://dx.doi.org/10.1182/bloodadvances.2019000848] [PMID: 31851760]
[102]
Wang D, Zhang G, Gu 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(4): e175-9.
[http://dx.doi.org/10.3324/haematol.2019.219089] [PMID: 31296582]
[103]
Slaymaker IM, Gao L, Zetsche B, Scott DA, Yan WX, Zhang F. Rationally engineered Cas9 nucleases with improved specificity. Science 2016; 351(6268): 84-8.
[http://dx.doi.org/10.1126/science.aad5227] [PMID: 26628643]
[104]
Kleinstiver BP, Pattanayak V, Prew MS, et al. High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects. Nature 2016; 529(7587): 490-5.
[http://dx.doi.org/10.1038/nature16526] [PMID: 26735016]
[105]
Scott T, Urak R, Soemardy C, Morris KV. Improved Cas9 activity by specific modifications of the tracrRNA. Sci Rep 2019; 9(1): 16104.
[http://dx.doi.org/10.1038/s41598-019-52616-5] [PMID: 31695072]
[106]
Jayavaradhan R, Pillis DM, Goodman M, et al. CRISPR-Cas9 fusion to dominant-negative 53BP1 enhances HDR and inhibits NHEJ specifically at Cas9 target sites. Nat Commun 2019; 10(1): 2866.
[http://dx.doi.org/10.1038/s41467-019-10735-7] [PMID: 31253785]
[107]
Kim S, Kim D, Cho SW, Kim J, Kim JS. Highly efficient RNA-guided genome editing in human cells via delivery of purified Cas9 ribonucleoproteins. Genome Res 2014; 24(6): 1012-9.
[http://dx.doi.org/10.1101/gr.171322.113] [PMID: 24696461]
[108]
Hendel A, Bak RO, Clark JT, et al. Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells. Nat Biotechnol 2015; 33(9): 985-9.
[http://dx.doi.org/10.1038/nbt.3290] [PMID: 26121415]
[109]
Yu Y, Guo Y, Tian Q, et al. An efficient gene knock-in strategy using 5′-modified double-stranded DNA donors with short homology arms. Nat Chem Biol 2020; 16(4): 387-90.
[http://dx.doi.org/10.1038/s41589-019-0432-1] [PMID: 31873222]
[110]
Bolukbasi MF, Gupta A, Wolfe SA. Creating and evaluating accurate CRISPR-Cas9 scalpels for genomic surgery. Nat Methods 2016; 13(1): 41-50.
[http://dx.doi.org/10.1038/nmeth.3684] [PMID: 26716561]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 2
Year: 2020
Page: [142 - 151]
Pages: 10
DOI: 10.2174/1566523220666200806110849
Price: $65

Article Metrics

PDF: 55
HTML: 3