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AAV Vector-Mediated Liver Gene Therapy and Its Implementation for Hemophilia

  • Hiroaki Mizukami
  • Jun Mimuro
  • Tsukasa Ohmori
  • Yoichi Sakata
  • Keiya Ozawa

Abstract

Adeno-associated virus (AAV) vector is widely used in gene transfer purposes. Not only the experimental gene transfer but also applications toward disease therapy are promising. Numerous attempts are ongoing for this purpose. One of the most prominent examples is the sustained clinical benefit in hemophilia gene therapy targeting the liver. These successes have been brought chiefly by the progress in vectorology, especially capsid development. At present, one of the biggest issues is the presence of neutralizing antibody (NAb) against AAV vector capsid. Challenges have been made to conquer this problem. Although there are still some hurdles for wide clinical application, use of this vector will soon be a common practice for the treatment of suitable disease conditions.

Keywords

AAV vector Serotype Hemophilia Neutralizing antibody Empty capsid 

References

  1. 1.
    Atchison RW, Casto BC, Hammon WM. Adenovirus-Associated Defective Virus Particles. Science. 1965;149(3685):754–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Bantel-Schaal U. zur Hausen H. Characterization of the DNA of a defective human parvovirus isolated from a genital site. Virology. 1984;134(1):52–63.CrossRefPubMedGoogle Scholar
  3. 3.
    Rutledge EA, Halbert CL, Russell DW. Infectious clones and vectors derived from adeno-associated virus (AAV) serotypes other than AAV type 2. J Virol. 1998;72(1):309–19.PubMedCentralPubMedGoogle Scholar
  4. 4.
    Muramatsu S, Mizukami H, Young NS, Brown KE. Nucleotide sequencing and generation of an infectious clone of adeno- associated virus 3. Virology. 1996;221(1):208–17.CrossRefPubMedGoogle Scholar
  5. 5.
    Chiorini JA, Yang L, Liu Y, Safer B, Kotin RM. Cloning of adeno-associated virus type 4 (AAV4) and generation of recombinant AAV4 particles. J Virol. 1997;71(9):6823–33.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Bantel-Schaal U, Delius H, Schmidt R. zur Hausen H. Human adeno-associated virus type 5 is only distantly related to other known primate helper-dependent parvoviruses. J Virol. 1999;73(2):939–47.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Chiorini JA, Kim F, Yang L, Kotin RM. Cloning and characterization of adeno-associated virus type 5. J Virol. 1999;73(2):1309–19.PubMedCentralPubMedGoogle Scholar
  8. 8.
    Xiao W, Chirmule N, Berta SC, McCullough B, Gao G, Wilson JM. Gene therapy vectors based on adeno-associated virus type 1. J Virol. 1999;73(5):3994–4003.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Gao GP, Alvira MR, Wang L, Calcedo R, Johnston J, Wilson JM. Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci U S A. 2002;99(18):11854–9. doi: 10.1073/pnas.182412299.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Gao G, Vandenberghe LH, Alvira MR, Lu Y, Calcedo R, Zhou X, et al. Clades of Adeno-associated viruses are widely disseminated in human tissues. J Virol. 2004;78(12):6381–8. doi: 10.1128/JVI.78.12.6381-6388.2004.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Bartel MA, Weinstein JR, Schaffer DV. Directed evolution of novel adeno-associated viruses for therapeutic gene delivery. Gene Ther. 2012;19(6):694–700. doi: 10.1038/gt.2012.20.CrossRefPubMedGoogle Scholar
  12. 12.
    Roberts HR, Escobar M, White GC II. Hemophilia A and hemophilia B. In: Lichtman MA, Beutler E, Kipps TJ, Seligson U, Kaushansky K, Prchal JT, editor. Williams hematology. 7 ed.: McGraw-Hill Medical; 2006. p. 1867–86.Google Scholar
  13. 13.
    High KA. The gene therapy journey for hemophilia: are we there yet? Hematology. 2012;2012:375–81. doi: 10.1182/asheducation-2012.1.375.PubMedGoogle Scholar
  14. 14.
    Manno CS, Chew AJ, Hutchison S, Larson PJ, Herzog RW, Arruda VR et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood. 2003;101(8):2963–72. doi: 10.1182/blood-2002-10-3296 2002-10-3296 [pii].
  15. 15.
    Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ 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. doi:nm1358 [pii]  10.1038/nm1358.
  16. 16.
    Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365(25):2357–65. doi: 10.1056/NEJMoa1108046.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Muramatsu S, Fujimoto K, Kato S, Mizukami H, Asari S, Ikeguchi K et al. A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson’s disease. Molecular therapy : the journal of the American Society of Gene Therapy. 2010;18(9):1731–5. doi:mt2010135 [pii]  10.1038/mt.2010.135.
  18. 18.
    Chenuaud P, Larcher T, Rabinowitz JE, Provost N, Cherel Y, Casadevall N et al. Autoimmune anemia in macaques following erythropoietin gene therapy. Blood. 2004;103(9):3303–4. doi: 10.1182/blood-2003-11-3845 2003-11-3845 [pii].
  19. 19.
    Gao G, Lebherz C, Weiner DJ, Grant R, Calcedo R, McCullough B et al. Erythropoietin gene therapy leads to autoimmune anemia in macaques. Blood. 2004;103(9):3300–2. doi: 10.1182/blood-2003-11-3852 2003-11-3852 [pii].
  20. 20.
    Gregorevic P, Blankinship MJ, Allen JM, Crawford RW, Meuse L, Miller DG, et al. Systemic delivery of genes to striated muscles using adeno-associated viral vectors. Nat Med. 2004;10(8):828–34. doi: 10.1038/nm1085.PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Rodino-Klapac LR, Montgomery CL, Mendell JR, Chicoine LG. AAV-mediated gene therapy to the isolated limb in rhesus macaques. Methods Mol Biol. 2011;709:287–98. doi: 10.1007/978-1-61737-982-6_19.CrossRefPubMedGoogle Scholar
  22. 22.
    Gao G, Lu Y, Calcedo R, Grant RL, Bell P, Wang L, et al. Biology of AAV serotype vectors in liver-directed gene transfer to nonhuman primates. Mol Ther. 2006;13(1):77–87. doi: 10.1016/j.ymthe.2005.08.017.CrossRefPubMedGoogle Scholar
  23. 23.
    Scallan CD, Jiang H, Liu T, Patarroyo-White S, Sommer JM, Zhou S, et al. Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice. Blood. 2006;107(5):1810–7. doi: 10.1182/blood-2005-08-3229.CrossRefPubMedGoogle Scholar
  24. 24.
    Halbert CL, Miller AD, McNamara S, Emerson J, Gibson RL, Ramsey B, et al. Prevalence of neutralizing antibodies against adeno-associated virus (AAV) types 2, 5, and 6 in cystic fibrosis and normal populations: Implications for gene therapy using AAV vectors. Hum Gene Ther. 2006;17(4):440–7. doi: 10.1089/hum.2006.17.440.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Calcedo R, Vandenberghe LH, Gao G, Lin J, Wilson JM. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis. 2009;199(3):381–90. doi: 10.1086/595830.CrossRefPubMedGoogle Scholar
  26. 26.
    Boutin S, Monteilhet V, Veron P, Leborgne C, Benveniste O, Montus MF, 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. doi: 10.1089/hum.2009.182.CrossRefPubMedGoogle Scholar
  27. 27.
    Calcedo R, Morizono H, Wang L, McCarter R, He J, Jones D et al. Adeno-associated virus antibody profiles in newborns, children, and adolescents. Clin Vaccine Immunol. 2011;18(9):1586–8. doi:CVI.05107-11 [pii]  10.1128/CVI.05107-11.
  28. 28.
    Li C, Narkbunnam N, Samulski RJ, Asokan A, Hu G, Jacobson LJ, et al. Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia. Gene Ther. 2012;19(3):288–94. doi: 10.1038/gt.2011.90.CrossRefPubMedGoogle Scholar
  29. 29.
    Liu Q, Huang W, Zhao C, Zhang L, Meng S, Gao D, et al. The prevalence of neutralizing antibodies against AAV serotype 1 in healthy subjects in China: implications for gene therapy and vaccines using AAV1 vector. J Med Virol. 2013;85(9):1550–6. doi: 10.1002/jmv.23647.CrossRefPubMedGoogle Scholar
  30. 30.
    Liu Q, Huang W, Zhang H, Wang Y, Zhao J, Song A, et al. Neutralizing antibodies against AAV2, AAV5 and AAV8 in healthy and HIV-1-infected subjects in China: implications for gene therapy using AAV vectors. Gene Ther. 2014;21(8):732–8. doi: 10.1038/gt.2014.47.CrossRefPubMedGoogle Scholar
  31. 31.
    Mimuro J, Mizukami H, Shima M, Matsushita T, Taki M, Muto S, et al. The prevalence of neutralizing antibodies against adeno-associated virus capsids is reduced in young Japanese individuals. J Med Virol. 2014;86(11):1990–7. doi: 10.1002/jmv.23818.CrossRefPubMedGoogle Scholar
  32. 32.
    Monteilhet V, Saheb S, Boutin S, Leborgne C, Veron P, Montus MF, et al. A 10 patient case report on the impact of plasmapheresis upon neutralizing factors against adeno-associated virus (AAV) types 1, 2, 6, and 8. Molecular therapy : the journal of the American Society of Gene Therapy. 2011;19(11):2084–91. doi: 10.1038/mt.2011.108.CrossRefGoogle Scholar
  33. 33.
    Mingozzi F, Chen Y, Edmonson SC, Zhou S, Thurlings RM, Tak PP, et al. Prevalence and pharmacological modulation of humoral immunity to AAV vectors in gene transfer to synovial tissue. Gene Ther. 2013;20(4):417–24. doi: 10.1038/gt.2012.55.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Mimuro J, Mizukami H, Hishikawa S, Ikemoto T, Ishiwata A, Sakata A, et al. Minimizing the inhibitory effect of neutralizing antibody for efficient gene expression in the liver with adeno-associated virus 8 vectors. Molecular therapy : the journal of the American Society of Gene Therapy. 2013;21(2):318–23. doi: 10.1038/mt.2012.258.CrossRefGoogle Scholar
  35. 35.
    Fagone P, Wright JF, Nathwani AC, Nienhuis AW, Davidoff AM, Gray JT. Systemic errors in quantitative polymerase chain reaction titration of self-complementary adeno-associated viral vectors and improved alternative methods. Human Gene Ther Methods. 2012;23(1):1–7. doi: 10.1089/hgtb.2011.104.CrossRefGoogle Scholar
  36. 36.
    Cheng B, Ling C, Dai Y, Lu Y, Glushakova LG, Gee SW, et al. Development of optimized AAV3 serotype vectors: mechanism of high-efficiency transduction of human liver cancer cells. Gene Ther. 2012;19(4):375–84. doi: 10.1038/gt.2011.105.PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Lisowski L, Dane AP, Chu K, Zhang Y, Cunningham SC, Wilson EM, et al. Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature. 2014;506(7488):382–6. doi: 10.1038/nature12875.PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Mingozzi F, Anguela XM, Pavani G, Chen Y, Davidson RJ, Hui DJ et al. Overcoming preexisting humoral immunity to AAV using capsid decoys. Science translational medicine. 2013;5(194):194ra92. doi: 10.1126/scitranslmed.3005795
  39. 39.
    Lock M, McGorray S, Auricchio A, Ayuso E, Beecham EJ, Blouin-Tavel V, et al. Characterization of a recombinant adeno-associated virus type 2 Reference Standard Material. Hum Gene Ther. 2010;21(10):1273–85. doi: 10.1089/hum.2009.223.PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Ayuso E, Blouin V, Lock M, McGorray S, Leon X, Alvira MR, et al. Manufacturing and characterization of a recombinant adeno-associated virus type 8 reference standard material. Hum Gene Ther. 2014;25(11):977–87. doi: 10.1089/hum.2014.057.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Japan 2016

Authors and Affiliations

  • Hiroaki Mizukami
    • 1
  • Jun Mimuro
    • 2
    • 3
  • Tsukasa Ohmori
    • 2
  • Yoichi Sakata
    • 2
  • Keiya Ozawa
    • 1
    • 4
  1. 1.Division of Genetic Therapeutics, Center for Molecular MedicineJichi Medical UniversityShimotsukeJapan
  2. 2.Division of Cell and Molecular Medicine, Center for Molecular MedicineJichi Medical UniversityShimotsukeJapan
  3. 3.Department of Internal MedicineIshibashi General HospitalShimotsukeJapan
  4. 4.IMSUT Hospital, The Institute of Medical ScienceThe University of TokyoTokyoJapan

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