Skip to main content
SpringerLink
Log in

AAV-Mediated Gene Delivery to the Liver: Overview of Current Technologies and Methods

  • Protocol
  • First Online:
Adeno-Associated Virus Vectors

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1950))

Abstract

Adeno-associated virus (AAV) vectors to treat liver-specific genetic diseases are the focus of several ongoing clinical trials. The ability to give a peripheral injection of virus that will successfully target the liver is one of many attractive features of this technology. Although initial studies of AAV liver gene transfer revealed some limitations, extensive animal modeling and further clinical development have helped solve some of these issues, resulting in several successful clinical trials that have reached curative levels of clotting factor expression in hemophilia. Looking beyond gene replacement, recent technologies offer the possibility for AAV liver gene transfer to directly repair deficient genes and potentially treat autoimmune disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Dunbar CE, High KA, Joung JK, Kohn DB, Ozawa K, Sadelain M (2018) Gene therapy comes of age. Science 359(6372). https://doi.org/10.1126/science.aan4672

    Article  PubMed  Google Scholar 

  2. FDA approves hereditary blindness gene therapy (2018) Nat Biotechnol 36(1):6. https://doi.org/10.1038/nbt0118-6a

  3. Rangarajan S, Walsh L, Lester W, Perry D, Madan B, Laffan M, Yu H, Vettermann C, Pierce GF, Wong WY, Pasi KJ (2017) AAV5-factor VIII gene transfer in severe hemophilia A. N Engl J Med 377(26):2519–2530. https://doi.org/10.1056/NEJMoa1708483

    Article  CAS  PubMed  Google Scholar 

  4. George LA, Sullivan SK, Giermasz A, Rasko JEJ, Samelson-Jones BJ, Ducore J, Cuker A, Sullivan LM, Majumdar S, Teitel J, McGuinn CE, Ragni MV, Luk AY, Hui D, Wright JF, Chen Y, Liu Y, Wachtel K, Winters A, Tiefenbacher S, Arruda VR, van der Loo JCM, Zelenaia O, Takefman D, Carr ME, Couto LB, Anguela XM, High KA (2017) Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med 377(23):2215–2227. https://doi.org/10.1056/NEJMoa1708538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Colella P, Ronzitti G, Mingozzi F (2018) Emerging issues in AAV-mediated in vivo gene therapy. Mol Ther Methods Clin Dev 8:87–104. https://doi.org/10.1016/j.omtm.2017.11.007

    Article  CAS  PubMed  Google Scholar 

  6. Mingozzi F, Maus MV, Hui DJ, Sabatino DE, Murphy SL, Rasko JE, Ragni MV, Manno CS, Sommer J, Jiang H, Pierce GF, Ertl HC, High KA (2007) CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nat Med 13(4):419–422. https://doi.org/10.1038/nm1549

    Article  CAS  PubMed  Google Scholar 

  7. Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, Chowdary P, Riddell A, Pie AJ, Harrington C, O’Beirne J, Smith K, Pasi J, Glader B, Rustagi P, Ng CY, Kay MA, Zhou J, Spence Y, Morton CL, Allay J, Coleman J, Sleep S, Cunningham JM, Srivastava D, Basner-Tschakarjan E, Mingozzi F, High KA, Gray JT, Reiss UM, Nienhuis AW, Davidoff AM (2011) Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 365(25):2357–2365. https://doi.org/10.1056/NEJMoa1108046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ertl HCJ, High KA (2017) 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 28(4):328–337. https://doi.org/10.1089/hum.2016.172

    Article  CAS  PubMed  Google Scholar 

  9. Gordillo M, Evans T, Gouon-Evans V (2015) Orchestrating liver development. Development 142(12):2094–2108. https://doi.org/10.1242/dev.114215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kattenhorn LM, Tipper CH, Stoica L, Geraghty DS, Wright TL, Clark KR, Wadsworth SC (2016) Adeno-associated virus gene therapy for liver disease. Hum Gene Ther 27(12):947–961. https://doi.org/10.1089/hum.2016.160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, Della Peruta M, Lheriteau E, Patel N, Raj D, Riddell A, Pie J, Rangarajan S, Bevan D, Recht M, Shen YM, Halka KG, Basner-Tschakarjan E, Mingozzi F, High KA, Allay J, Kay MA, Ng CY, Zhou J, Cancio M, Morton CL, Gray JT, Srivastava D, Nienhuis AW, Davidoff AM (2014) Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 371(21):1994–2004. https://doi.org/10.1056/NEJMoa1407309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Niemeyer GP, Herzog RW, Mount J, Arruda VR, Tillson DM, Hathcock J, van Ginkel FW, High KA, Lothrop CD Jr (2009) Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy. Blood 113(4):797–806. https://doi.org/10.1182/blood-2008-10-181479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rogers GL, Herzog RW (2015) Gene therapy for hemophilia. Front Biosci (Landmark Ed) 20:556–603

    Article  CAS  Google Scholar 

  14. Mingozzi F, Liu YL, Dobrzynski E, Kaufhold A, Liu JH, Wang Y, Arruda VR, High KA, Herzog RW (2003) Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer. J Clin Invest 111(9):1347–1356. https://doi.org/10.1172/JCI16887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dobrzynski E, Fitzgerald JC, Cao O, Mingozzi F, Wang L, Herzog RW (2006) Prevention of cytotoxic T lymphocyte responses to factor IX-expressing hepatocytes by gene transfer-induced regulatory T cells. Proc Natl Acad Sci U S A 103(12):4592–4597. https://doi.org/10.1073/pnas.0508685103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kumar SRP, Hoffman BE, Terhorst C, de Jong YP, Herzog RW (2017) The balance between CD8(+) T cell-mediated clearance of AAV-encoded antigen in the liver and tolerance is dependent on the vector dose. Mol Ther 25(4):880–891. https://doi.org/10.1016/j.ymthe.2017.02.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Martino AT, Nayak S, Hoffman BE, Cooper M, Liao G, Markusic DM, Byrne BJ, Terhorst C, Herzog RW (2009) Tolerance induction to cytoplasmic beta-galactosidase by hepatic AAV gene transfer: implications for antigen presentation and immunotoxicity. PLoS One 4(8):e6376. https://doi.org/10.1371/journal.pone.0006376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. LoDuca PA, Hoffman BE, Herzog RW (2009) Hepatic gene transfer as a means of tolerance induction to transgene products. Curr Gene Ther 9(2):104–114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Keeler GD, Markusic DM, Hoffman BE (2017) Liver induced transgene tolerance with AAV vectors. Cell Immunol. https://doi.org/10.1016/j.cellimm.2017.12.002

  20. Atchison RW, Casto BC, Hammon WM (1965) Adenovirus-associated defective virus particles. Science 149(3685):754–756

    Article  CAS  PubMed  Google Scholar 

  21. Samulski RJ, Berns KI, Tan M, Muzyczka N (1982) Cloning of adeno-associated virus into pBR322: rescue of intact virus from the recombinant plasmid in human cells. Proc Natl Acad Sci U S A 79(6):2077–2081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Srivastava A, Lusby EW, Berns KI (1983) Nucleotide sequence and organization of the adeno-associated virus 2 genome. J Virol 45(2):555–564

    CAS  PubMed  PubMed Central  Google Scholar 

  23. McLaughlin SK, Collis P, Hermonat PL, Muzyczka N (1988) Adeno-associated virus general transduction vectors: analysis of proviral structures. J Virol 62(6):1963–1973

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Grimm D, Pandey K, Nakai H, Storm TA, Kay MA (2006) Liver transduction with recombinant adeno-associated virus is primarily restricted by capsid serotype not vector genotype. J Virol 80(1):426–439. https://doi.org/10.1128/JVI.80.1.426-439.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Samulski RJ, Srivastava A, Berns KI, Muzyczka N (1983) Rescue of adeno-associated virus from recombinant plasmids: gene correction within the terminal repeats of AAV. Cell 33(1):135–143

    Article  CAS  PubMed  Google Scholar 

  26. Xiao X, Li J, Samulski RJ (1998) Production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus. J Virol 72(3):2224–2232

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Matsushita T, Elliger S, Elliger C, Podsakoff G, Villarreal L, Kurtzman GJ, Iwaki Y, Colosi P (1998) Adeno-associated virus vectors can be efficiently produced without helper virus. Gene Ther 5(7):938–945. https://doi.org/10.1038/sj.gt.3300680

    Article  CAS  PubMed  Google Scholar 

  28. Grimm D, Kern A, Rittner K, Kleinschmidt JA (1998) Novel tools for production and purification of recombinant adenoassociated virus vectors. Hum Gene Ther 9(18):2745–2760. https://doi.org/10.1089/hum.1998.9.18-2745

    Article  CAS  PubMed  Google Scholar 

  29. Kohlbrenner E, Aslanidi G, Nash K, Shklyaev S, Campbell-Thompson M, Byrne BJ, Snyder RO, Muzyczka N, Warrington KH Jr, Zolotukhin S (2005) Successful production of pseudotyped rAAV vectors using a modified baculovirus expression system. Mol Ther 12(6):1217–1225. https://doi.org/10.1016/j.ymthe.2005.08.018

    Article  CAS  PubMed  Google Scholar 

  30. Gray JT, Zolotukhin S (2011) Design and construction of functional AAV vectors. Methods Mol Biol 807:25–46. https://doi.org/10.1007/978-1-61779-370-7_2

    Article  CAS  PubMed  Google Scholar 

  31. Mietzsch M, Grasse S, Zurawski C, Weger S, Bennett A, Agbandje-McKenna M, Muzyczka N, Zolotukhin S, Heilbronn R (2014) OneBac: platform for scalable and high-titer production of adeno-associated virus serotype 1-12 vectors for gene therapy. Hum Gene Ther 25(3):212–222. https://doi.org/10.1089/hum.2013.184

    Article  CAS  PubMed  Google Scholar 

  32. Wang L, Blouin V, Brument N, Bello-Roufai M, Francois A (2011) Production and purification of recombinant adeno-associated vectors. Methods Mol Biol 807:361–404. https://doi.org/10.1007/978-1-61779-370-7_16

    Article  CAS  PubMed  Google Scholar 

  33. Zaiss AK, Liu Q, Bowen GP, Wong NC, Bartlett JS, Muruve DA (2002) Differential activation of innate immune responses by adenovirus and adeno-associated virus vectors. J Virol 76(9):4580–4590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nakai H, Yant SR, Storm TA, Fuess S, Meuse L, Kay MA (2001) Extrachromosomal recombinant adeno-associated virus vector genomes are primarily responsible for stable liver transduction in vivo. J Virol 75(15):6969–6976. https://doi.org/10.1128/JVI.75.15.6969-6976.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Koeberl DD, Alexander IE, Halbert CL, Russell DW, Miller AD (1997) Persistent expression of human clotting factor IX from mouse liver after intravenous injection of adeno-associated virus vectors. Proc Natl Acad Sci U S A 94(4):1426–1431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ponnazhagan S, Mukherjee P, Yoder MC, Wang XS, Zhou SZ, Kaplan J, Wadsworth S, Srivastava A (1997) Adeno-associated virus 2-mediated gene transfer in vivo: organ-tropism and expression of transduced sequences in mice. Gene 190(1):203–210

    Article  CAS  PubMed  Google Scholar 

  37. Snyder RO, Miao CH, Patijn GA, Spratt SK, Danos O, Nagy D, Gown AM, Winther B, Meuse L, Cohen LK, Thompson AR, Kay MA (1997) Persistent and therapeutic concentrations of human factor IX in mice after hepatic gene transfer of recombinant AAV vectors. Nat Genet 16(3):270–276. https://doi.org/10.1038/ng0797-270

    Article  CAS  PubMed  Google Scholar 

  38. Miao CH, Nakai H, Thompson AR, Storm TA, Chiu W, Snyder RO, Kay MA (2000) Nonrandom transduction of recombinant adeno-associated virus vectors in mouse hepatocytes in vivo: cell cycling does not influence hepatocyte transduction. J Virol 74(8):3793–3803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nakai H, Thomas CE, Storm TA, Fuess S, Powell S, Wright JF, Kay MA (2002) A limited number of transducible hepatocytes restricts a wide-range linear vector dose response in recombinant adeno-associated virus-mediated liver transduction. J Virol 76(22):11343–11349. https://doi.org/10.1128/JVI.76.22.11343-11349.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gao G, Vandenberghe LH, Alvira MR, Lu Y, Calcedo R, Zhou X, Wilson JM (2004) Clades of adeno-associated viruses are widely disseminated in human tissues. J Virol 78(12):6381–6388. https://doi.org/10.1128/JVI.78.12.6381-6388.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Agbandje-McKenna M, Kleinschmidt J (2011) AAV capsid structure and cell interactions. Methods Mol Biol 807:47–92. https://doi.org/10.1007/978-1-61779-370-7_3

    Article  CAS  PubMed  Google Scholar 

  42. Rabinowitz JE, Rolling F, Li C, Conrath H, Xiao W, Xiao X, Samulski RJ (2002) Cross-packaging of a single adeno-associated virus (AAV) type 2 vector genome into multiple AAV serotypes enables transduction with broad specificity. J Virol 76(2):791–801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gao GP, Alvira MR, Wang L, Calcedo R, Johnston J, Wilson JM (2002) Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci U S A 99(18):11854–11859. https://doi.org/10.1073/pnas.182412299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zincarelli C, Soltys S, Rengo G, Rabinowitz JE (2008) Analysis of AAV serotypes 1-9 mediated gene expression and tropism in mice after systemic injection. Mol Ther 16(6):1073–1080. https://doi.org/10.1038/mt.2008.76

    Article  CAS  PubMed  Google Scholar 

  45. Vercauteren K, Hoffman BE, Zolotukhin I, Keeler GD, Xiao JW, Basner-Tschakarjan E, High KA, Ertl HC, Rice CM, Srivastava A, de Jong YP, Herzog RW (2016) Superior in vivo transduction of human hepatocytes using engineered AAV3 capsid. Mol Ther 24(6):1042–1049. https://doi.org/10.1038/mt.2016.61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li S, Ling C, Zhong L, Li M, Su Q, He R, Tang Q, Greiner DL, Shultz LD, Brehm MA, Flotte TR, Mueller C, Srivastava A, Gao G (2015) Efficient and targeted transduction of nonhuman primate liver with systemically delivered optimized AAV3B vectors. Mol Ther 23(12):1867–1876. https://doi.org/10.1038/mt.2015.174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhao W, Zhong L, Wu J, Chen L, Qing K, Weigel-Kelley KA, Larsen SH, Shou W, Warrington KH Jr, Srivastava A (2006) Role of cellular FKBP52 protein in intracellular trafficking of recombinant adeno-associated virus 2 vectors. Virology 353(2):283–293. https://doi.org/10.1016/j.virol.2006.04.042

    Article  CAS  PubMed  Google Scholar 

  48. Markusic DM, Herzog RW, Aslanidi GV, Hoffman BE, Li B, Li M, Jayandharan GR, Ling C, Zolotukhin I, Ma W, Zolotukhin S, Srivastava A, Zhong L (2010) High-efficiency transduction and correction of murine hemophilia B using AAV2 vectors devoid of multiple surface-exposed tyrosines. Mol Ther 18(12):2048–2056. https://doi.org/10.1038/mt.2010.172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhong L, Li B, Mah CS, Govindasamy L, Agbandje-McKenna M, Cooper M, Herzog RW, Zolotukhin I, Warrington KH Jr, Weigel-Van Aken KA, Hobbs JA, Zolotukhin S, Muzyczka N, Srivastava A (2008) Next generation of adeno-associated virus 2 vectors: point mutations in tyrosines lead to high-efficiency transduction at lower doses. Proc Natl Acad Sci U S A 105(22):7827–7832. https://doi.org/10.1073/pnas.0802866105

    Article  PubMed  PubMed Central  Google Scholar 

  50. Martino AT, Basner-Tschakarjan E, Markusic DM, Finn JD, Hinderer C, Zhou S, Ostrov DA, Srivastava A, Ertl HC, Terhorst C, High KA, Mingozzi F, Herzog RW (2013) Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsid-specific CD8+ T cells. Blood 121(12):2224–2233. https://doi.org/10.1182/blood-2012-10-460733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Maheshri N, Koerber JT, Kaspar BK, Schaffer DV (2006) Directed evolution of adeno-associated virus yields enhanced gene delivery vectors. Nat Biotechnol 24(2):198–204. https://doi.org/10.1038/nbt1182

    Article  CAS  PubMed  Google Scholar 

  52. Grimm D, Lee JS, Wang L, Desai T, Akache B, Storm TA, Kay MA (2008) In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J Virol 82(12):5887–5911. https://doi.org/10.1128/JVI.00254-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lisowski L, Dane AP, Chu K, Zhang Y, Cunningham SC, Wilson EM, Nygaard S, Grompe M, Alexander IE, Kay MA (2014) Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature 506(7488):382–386. https://doi.org/10.1038/nature12875

    Article  CAS  PubMed  Google Scholar 

  54. Azuma H, Paulk N, Ranade A, Dorrell C, Al-Dhalimy M, Ellis E, Strom S, Kay MA, Finegold M, Grompe M (2007) Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice. Nat Biotechnol 25(8):903–910. https://doi.org/10.1038/nbt1326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Paulk NK, Pekrun K, Zhu E, Nygaard S, Li B, Xu J, Chu K, Leborgne C, Dane AP, Haft A, Zhang Y, Zhang F, Morton C, Valentine MB, Davidoff AM, Nathwani AC, Mingozzi F, Grompe M, Alexander IE, Lisowski L, Kay MA (2018) Bioengineered AAV capsids with combined high human liver transduction in vivo and unique humoral seroreactivity. Mol Ther 26(1):289–303. https://doi.org/10.1016/j.ymthe.2017.09.021

    Article  CAS  PubMed  Google Scholar 

  56. Marsic D, Govindasamy L, Currlin S, Markusic DM, Tseng YS, Herzog RW, Agbandje-McKenna M, Zolotukhin S (2014) Vector design Tour de Force: integrating combinatorial and rational approaches to derive novel adeno-associated virus variants. Mol Ther 22(11):1900–1909. https://doi.org/10.1038/mt.2014.139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Summerford C, Samulski RJ (1998) Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions. J Virol 72(2):1438–1445

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Ferrari FK, Samulski T, Shenk T, Samulski RJ (1996) Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors. J Virol 70(5):3227–3234

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Davidoff AM, Gray JT, Ng CY, Zhang Y, Zhou J, Spence Y, Bakar Y, Nathwani AC (2005) Comparison of the ability of adeno-associated viral vectors pseudotyped with serotype 2, 5, and 8 capsid proteins to mediate efficient transduction of the liver in murine and nonhuman primate models. Mol Ther 11(6):875–888. https://doi.org/10.1016/j.ymthe.2004.12.022

    Article  CAS  PubMed  Google Scholar 

  60. Wang J, Xie J, Lu H, Chen L, Hauck B, Samulski RJ, Xiao W (2007) Existence of transient functional double-stranded DNA intermediates during recombinant AAV transduction. Proc Natl Acad Sci U S A 104(32):13104–13109. https://doi.org/10.1073/pnas.0702778104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. McCarty DM, Monahan PE, Samulski RJ (2001) Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis. Gene Ther 8(16):1248–1254. https://doi.org/10.1038/sj.gt.3301514

    Article  CAS  PubMed  Google Scholar 

  62. McCarty DM, Fu H, Monahan PE, Toulson CE, Naik P, Samulski RJ (2003) Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo. Gene Ther 10(26):2112–2118. https://doi.org/10.1038/sj.gt.3302134

    Article  CAS  PubMed  Google Scholar 

  63. Wang Z, Ma HI, Li J, Sun L, Zhang J, Xiao X (2003) Rapid and highly efficient transduction by double-stranded adeno-associated virus vectors in vitro and in vivo. Gene Ther 10(26):2105–2111. https://doi.org/10.1038/sj.gt.3302133

    Article  CAS  PubMed  Google Scholar 

  64. Miesbach W, Meijer K, Coppens M, Kampmann P, Klamroth R, Schutgens R, Tangelder M, Castaman G, Schwable J, Bonig H, Seifried E, Cattaneo F, Meyer C, Leebeek FWG (2018) Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood 131(9):1022–1031. https://doi.org/10.1182/blood-2017-09-804419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Herzog RW (2017) Complexity of immune responses to AAV transgene products—example of factor IX. Cell Immunol. https://doi.org/10.1016/j.cellimm.2017.05.006

  66. Miao CH, Ohashi K, Patijn GA, Meuse L, Ye X, Thompson AR, Kay MA (2000) Inclusion of the hepatic locus control region, an intron, and untranslated region increases and stabilizes hepatic factor IX gene expression in vivo but not in vitro. Mol Ther 1(6):522–532. https://doi.org/10.1006/mthe.2000.0075

    Article  CAS  PubMed  Google Scholar 

  67. Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, Ozelo MC, Hoots K, Blatt P, Konkle B, Dake M, Kaye R, Razavi M, Zajko A, Zehnder J, Rustagi PK, Nakai H, Chew A, Leonard D, Wright JF, Lessard RR, Sommer JM, Tigges M, Sabatino D, Luk A, Jiang H, Mingozzi F, Couto L, Ertl HC, High KA, Kay MA (2006) Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 12(3):342–347. https://doi.org/10.1038/nm1358

    Article  CAS  PubMed  Google Scholar 

  68. Nathwani AC, Gray JT, Ng CY, Zhou J, Spence Y, Waddington SN, Tuddenham EG, Kemball-Cook G, McIntosh J, Boon-Spijker M, Mertens K, Davidoff AM (2006) Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver. Blood 107(7):2653–2661. https://doi.org/10.1182/blood-2005-10-4035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. McIntosh J, Lenting PJ, Rosales C, Lee D, Rabbanian S, Raj D, Patel N, Tuddenham EG, Christophe OD, McVey JH, Waddington S, Nienhuis AW, Gray JT, Fagone P, Mingozzi F, Zhou SZ, High KA, Cancio M, Ng CY, Zhou J, Morton CL, Davidoff AM, Nathwani AC (2013) Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant. Blood 121(17):3335–3344. https://doi.org/10.1182/blood-2012-10-462200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Costa RH, Grayson DR, Darnell JEJ (1989) Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes. Mol Cell Biol 9(4):1415–1425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Chuah MK, Petrus I, De Bleser P, Le Guiner C, Gernoux G, Adjali O, Nair N, Willems J, Evens H, Rincon MY, Matrai J, Di Matteo M, Samara-Kuko E, Yan B, Acosta-Sanchez A, Meliani A, Cherel G, Blouin V, Christophe O, Moullier P, Mingozzi F, VandenDriessche T (2014) Liver-specific transcriptional modules identified by genome-wide in silico analysis enable efficient gene therapy in mice and non-human primates. Mol Ther 22(9):1605–1613. https://doi.org/10.1038/mt.2014.114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Nair N, Rincon MY, Evens H, Sarcar S, Dastidar S, Samara-Kuko E, Ghandeharian O, Man Viecelli H, Thony B, De Bleser P, VandenDriessche T, Chuah MK (2014) Computationally designed liver-specific transcriptional modules and hyperactive factor IX improve hepatic gene therapy. Blood 123(20):3195–3199. https://doi.org/10.1182/blood-2013-10-534032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Brown HC, Zakas PM, George SN, Parker ET, Spencer HT, Doering CB (2018) Target-cell-directed bioengineering approaches for gene therapy of hemophilia A. Mol Ther Methods Clin Dev 9:57–69. https://doi.org/10.1016/j.omtm.2018.01.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Sack BK, Merchant S, Markusic DM, Nathwani AC, Davidoff AM, Byrne BJ, Herzog RW (2012) Transient B cell depletion or improved transgene expression by codon optimization promote tolerance to factor VIII in gene therapy. PLoS One 7(5):e37671. https://doi.org/10.1371/journal.pone.0037671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Vandamme C, Adjali O, Mingozzi F (2017) Unraveling the complex story of immune responses to AAV vectors trial after trial. Hum Gene Ther 28(11):1061–1074. https://doi.org/10.1089/hum.2017.150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Martino AT, Suzuki M, Markusic DM, Zolotukhin I, Ryals RC, Moghimi B, Ertl HC, Muruve DA, Lee B, Herzog RW (2011) The genome of self-complementary adeno-associated viral vectors increases Toll-like receptor 9-dependent innate immune responses in the liver. Blood 117(24):6459–6468. https://doi.org/10.1182/blood-2010-10-314518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rogers GL, Shirley JL, Zolotukhin I, Kumar SRP, Sherman A, Perrin GQ, Hoffman BE, Srivastava A, Basner-Tschakarjan E, Wallet MA, Terhorst C, Biswas M, Herzog RW (2017) Plasmacytoid and conventional dendritic cells cooperate in crosspriming AAV capsid-specific CD8(+) T cells. Blood 129(24):3184–3195. https://doi.org/10.1182/blood-2016-11-751040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Faust SM, Bell P, Cutler BJ, Ashley SN, Zhu Y, Rabinowitz JE, Wilson JM (2013) CpG-depleted adeno-associated virus vectors evade immune detection. J Clin Invest 123(7):2994–3001. https://doi.org/10.1172/JCI68205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Sferra TJ, Backstrom K, Wang C, Rennard R, Miller M, Hu Y (2004) Widespread correction of lysosomal storage following intrahepatic injection of a recombinant adeno-associated virus in the adult MPS VII mouse. Mol Ther 10(3):478–491. https://doi.org/10.1016/j.ymthe.2004.05.029

    Article  CAS  PubMed  Google Scholar 

  80. Chandler RJ, Chandrasekaran S, Carrillo-Carrasco N, Senac JS, Hofherr SE, Barry MA, Venditti CP (2011) Adeno-associated virus serotype 8 gene transfer rescues a neonatal lethal murine model of propionic acidemia. Hum Gene Ther 22(4):477–481. https://doi.org/10.1089/hum.2010.164

    Article  CAS  PubMed  Google Scholar 

  81. Sherman A, Schlachterman A, Cooper M, Merricks EP, Raymer RA, Bellinger DA, Herzog RW, Nichols TC (2014) Portal vein delivery of viral vectors for gene therapy for hemophilia, 1114. Humana Press, Totowa, pp 413–426. https://doi.org/10.1007/978-1-62703-761-7_27

    Book  Google Scholar 

  82. Nakai H, Herzog RW, Hagstrom JN, Walter J, Kung SH, Yang EY, Tai SJ, Iwaki Y, Kurtzman GJ, Fisher KJ, Colosi P, Couto LB, High KA (1998) Adeno-associated viral vector-mediated gene transfer of human blood coagulation factor IX into mouse liver. Blood 91(12):4600–4607

    CAS  PubMed  Google Scholar 

  83. Fisher KJ, Gao GP, Weitzman MD, DeMatteo R, Burda JF, Wilson JM (1996) Transduction with recombinant adeno-associated virus for gene therapy is limited by leading-strand synthesis. J Virol 70(1):520–532

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Zabaleta N, Salas D, Paramo M, Hommel M, Sier-Ferreira V, Hernandez-Alcoceba R, Prieto J, Bilbao JI, Gonzalez-Aseguinolaza G (2017) Improvement of adeno-associated virus-mediated liver transduction efficacy by regional administration in Macaca fascicularis. Hum Gene Ther Clin Dev 28(2):68–73. https://doi.org/10.1089/humc.2016.183

    Article  CAS  PubMed  Google Scholar 

  85. Cunningham SC, Dane AP, Spinoulas A, Alexander IE (2008) Gene delivery to the juvenile mouse liver using AAV2/8 vectors. Mol Ther 16(6):1081–1088. https://doi.org/10.1038/mt.2008.72

    Article  CAS  PubMed  Google Scholar 

  86. Lipshutz GS, Gruber CA, Cao Y, Hardy J, Contag CH, Gaensler KM (2001) In utero delivery of adeno-associated viral vectors: intraperitoneal gene transfer produces long-term expression. Mol Ther 3(3):284–292. https://doi.org/10.1006/mthe.2001.0267

    Article  CAS  PubMed  Google Scholar 

  87. Dane AP, Wowro SJ, Cunningham SC, Alexander IE (2013) Comparison of gene transfer to the murine liver following intraperitoneal and intraportal delivery of hepatotropic AAV pseudo-serotypes. Gene Ther 20(4):460–464. https://doi.org/10.1038/gt.2012.67

    Article  CAS  PubMed  Google Scholar 

  88. Ahmed SS, Li J, Godwin J, Gao G, Zhong L (2013) Gene transfer in the liver using recombinant adeno-associated virus. Curr Protoc Microbiol Chapter 14:Unit14D 16. https://doi.org/10.1002/9780471729259.mc14d06s29

    Article  Google Scholar 

  89. Yardeni T, Eckhaus M, Morris HD, Huizing M, Hoogstraten-Miller S (2011) Retro-orbital injections in mice. Lab Anim (NY) 40(5):155–160. https://doi.org/10.1038/laban0511-155

    Article  Google Scholar 

  90. Wang L, Wang H, Bell P, McCarter RJ, He J, Calcedo R, Vandenberghe LH, Morizono H, Batshaw ML, Wilson JM (2010) Systematic evaluation of AAV vectors for liver directed gene transfer in murine models. Mol Ther 18(1):118–125. https://doi.org/10.1038/mt.2009.246

    Article  CAS  PubMed  Google Scholar 

  91. Nakai H, Fuess S, Storm TA, Muramatsu S, Nara Y, Kay MA (2005) Unrestricted hepatocyte transduction with adeno-associated virus serotype 8 vectors in mice. J Virol 79(1):214–224. https://doi.org/10.1128/JVI.79.1.214-224.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cooper M, Nayak S, Hoffman BE, Terhorst C, Cao O, Herzog RW (2009) Improved induction of immune tolerance to factor IX by hepatic AAV-8 gene transfer. Hum Gene Ther 20(7):767–776. https://doi.org/10.1089/hum.2008.161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Sands MS (2011) AAV-mediated liver-directed gene therapy. Methods Mol Biol 807:141–157. https://doi.org/10.1007/978-1-61779-370-7_6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Palaschak B, Marsic D, Herzog RW, Zolotukhin S, Markusic DM (2017) An immune-competent murine model to study elimination of AAV-transduced hepatocytes by capsid-specific CD8(+) T cells. Mol Ther Methods Clin Dev 5:142–152. https://doi.org/10.1016/j.omtm.2017.04.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Daly TM, Vogler C, Levy B, Haskins ME, Sands MS (1999) Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease. Proc Natl Acad Sci U S A 96(5):2296–2300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. McKay TR, Rahim AA, Buckley SM, Ward NJ, Chan JK, Howe SJ, Waddington SN (2011) Perinatal gene transfer to the liver. Curr Pharm Des 17(24):2528–2541. https://doi.org/10.2174/138161211797247541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Davidoff AM, Ng CYC, Zhou JF, Spence Y, Nathwani AC (2003) Sex significantly influences transduction of murine liver by recombinant adeno-associated viral vectors through an androgen-dependent pathway. Blood 102(2):480–488. https://doi.org/10.1182/blood-2002-09-2889

    Article  CAS  PubMed  Google Scholar 

  98. Paneda A, Vanrell L, Mauleon I, Crettaz JS, Berraondo P, Timmermans EJ, Beattie SG, Twisk J, van Deventer S, Prieto J, Fontanellas A, Rodriguez-Pena MS, Gonzalez-Aseguinolaza G (2009) Effect of adeno-associated virus serotype and genomic structure on liver transduction and biodistribution in mice of both genders. Hum Gene Ther 20(8):908–917. https://doi.org/10.1089/hum.2009.031

    Article  CAS  PubMed  Google Scholar 

  99. Nathwani AC, Cochrane M, McIntosh J, Ng CY, Zhou J, Gray JT, Davidoff AM (2009) Enhancing transduction of the liver by adeno-associated viral vectors. Gene Ther 16(1):60–69. https://doi.org/10.1038/gt.2008.137

    Article  CAS  PubMed  Google Scholar 

  100. Berraondo P, Crettaz J, Ochoa L, Paneda A, Prieto J, Troconiz IF, Gonzalez-Aseguinolaza G (2006) Intrahepatic injection of recombinant adeno-associated virus serotype 2 overcomes gender-related differences in liver transduction. Hum Gene Ther 17(6):601–610. https://doi.org/10.1089/hum.2006.17.601

    Article  CAS  PubMed  Google Scholar 

  101. Ohashi K, Nakai H, Couto LB, Kay MA (2005) Modified infusion procedures affect recombinant adeno-associated virus vector type 2 transduction in the liver. Hum Gene Ther 16(3):299–306. https://doi.org/10.1089/hum.2005.16.299

    Article  CAS  PubMed  Google Scholar 

  102. Seppen J, Bakker C, de Jong B, Kunne C, van den Oever K, Vandenberghe K, de Waart R, Twisk J, Bosma P (2006) Adeno-associated virus vector serotypes mediate sustained correction of bilirubin UDP glucuronosyltransferase deficiency in rats. Mol Ther 13(6):1085–1092. https://doi.org/10.1016/j.ymthe.2006.01.014

    Article  CAS  PubMed  Google Scholar 

  103. Montenegro-Miranda PS, Paneda A, ten Bloemendaal L, Duijst S, de Waart DR, Gonzalez-Aseguinolaza G, Bosma PJ (2013) Adeno-associated viral vector serotype 5 poorly transduces liver in rat models. PLoS One 8(12):e82597. https://doi.org/10.1371/journal.pone.0082597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Sobrevals L, Enguita M, Rodriguez C, Gonzalez-Rojas J, Alzaguren P, Razquin N, Prieto J, Fortes P (2012) AAV vectors transduce hepatocytes in vivo as efficiently in cirrhotic as in healthy rat livers. Gene Ther 19(4):411–417. https://doi.org/10.1038/gt.2011.119

    Article  CAS  PubMed  Google Scholar 

  105. Ferla R, O’Malley T, Calcedo R, O’Donnell P, Wang P, Cotugno G, Claudiani P, Wilson JM, Haskins M, Auricchio A (2013) Gene therapy for mucopolysaccharidosis type VI is effective in cats without pre-existing immunity to AAV8. Hum Gene Ther 24(2):163–169. https://doi.org/10.1089/hum.2012.179

    Article  CAS  PubMed  Google Scholar 

  106. Cotugno G, Annunziata P, Tessitore A, O’Malley T, Capalbo A, Faella A, Bartolomeo R, O’Donnell P, Wang P, Russo F, Sleeper MM, Knox VW, Fernandez S, Levanduski L, Hopwood J, De Leonibus E, Haskins M, Auricchio A (2011) Long-term amelioration of feline Mucopolysaccharidosis VI after AAV-mediated liver gene transfer. Mol Ther 19(3):461–469. https://doi.org/10.1038/mt.2010.257

    Article  CAS  PubMed  Google Scholar 

  107. Hinderer C, Bell P, Gurda BL, Wang Q, Louboutin JP, Zhu Y, Bagel J, O’Donnell P, Sikora T, Ruane T, Wang P, Haskins ME, Wilson JM (2014) Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I. Proc Natl Acad Sci U S A 111(41):14894–14899. https://doi.org/10.1073/pnas.1413645111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Beaty RM, Jackson M, Peterson D, Bird A, Brown T, Benjamin DK Jr, Juopperi T, Kishnani P, Boney A, Chen YT, Koeberl DD (2002) Delivery of glucose-6-phosphatase in a canine model for glycogen storage disease, type Ia, with adeno-associated virus (AAV) vectors. Gene Ther 9(15):1015–1022. https://doi.org/10.1038/sj.gt.3301728

    Article  CAS  PubMed  Google Scholar 

  109. Mount JD, Herzog RW, Tillson DM, Goodman SA, Robinson N, McCleland ML, Bellinger D, Nichols TC, Arruda VR, Lothrop CD Jr, High KA (2002) Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy. Blood 99(8):2670–2676

    Article  CAS  PubMed  Google Scholar 

  110. Nichols TC, Whitford MH, Arruda VR, Stedman HH, Kay MA, High KA (2015) Translational data from adeno-associated virus-mediated gene therapy of hemophilia B in dogs. Hum Gene Ther Clin Dev 26(1):5–14. https://doi.org/10.1089/humc.2014.153

    Article  CAS  PubMed  Google Scholar 

  111. Callan MB, Haskins ME, Wang P, Zhou S, High KA, Arruda VR (2016) Successful phenotype improvement following gene therapy for severe hemophilia A in privately owned dogs. PLoS One 11(3):e0151800. https://doi.org/10.1371/journal.pone.0151800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Finn JD, Ozelo MC, Sabatino DE, Franck HW, Merricks EP, Crudele JM, Zhou S, Kazazian HH, Lillicrap D, Nichols TC, Arruda VR (2010) Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy. Blood 116(26):5842–5848. https://doi.org/10.1182/blood-2010-06-288001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Monahan PE, Lothrop CD, Sun J, Hirsch ML, Kafri T, Kantor B, Sarkar R, Tillson DM, Elia JR, Samulski RJ (2010) Proteasome inhibitors enhance gene delivery by AAV virus vectors expressing large genomes in hemophilia mouse and dog models: a strategy for broad clinical application. Mol Ther 18(11):1907–1916. https://doi.org/10.1038/mt.2010.170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Sabatino DE, Lange AM, Altynova ES, Sarkar R, Zhou S, Merricks EP, Franck HG, Nichols TC, Arruda VR, Kazazian HH Jr (2011) Efficacy and safety of long-term prophylaxis in severe hemophilia A dogs following liver gene therapy using AAV vectors. Mol Ther 19(3):442–449. https://doi.org/10.1038/mt.2010.240

    Article  CAS  PubMed  Google Scholar 

  115. Bell P, Gao G, Haskins ME, Wang L, Sleeper M, Wang H, Calcedo R, Vandenberghe LH, Chen SJ, Weisse C, Withnall E, Wilson JM (2011) Evaluation of adeno-associated viral vectors for liver-directed gene transfer in dogs. Hum Gene Ther 22(8):985–997. https://doi.org/10.1089/hum.2010.194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Majowicz A, Salas D, Zabaleta N, Rodriguez-Garcia E, Gonzalez-Aseguinolaza G, Petry H, Ferreira V (2017) Successful repeated hepatic gene delivery in mice and non-human primates achieved by sequential administration of AAV5(ch) and AAV1. Mol Ther 25(8):1831–1842. https://doi.org/10.1016/j.ymthe.2017.05.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gao GP, Lu Y, Sun X, Johnston J, Calcedo R, Grant R, Wilson JM (2006) High-level transgene expression in nonhuman primate liver with novel adeno-associated virus serotypes containing self-complementary genomes. J Virol 80(12):6192–6194. https://doi.org/10.1128/JVI.00526-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Nathwani AC, Gray JT, McIntosh J, Ng CY, Zhou J, Spence Y, Cochrane M, Gray E, Tuddenham EG, Davidoff AM (2007) Safe and efficient transduction of the liver after peripheral vein infusion of self-complementary AAV vector results in stable therapeutic expression of human FIX in nonhuman primates. Blood 109(4):1414–1421. https://doi.org/10.1182/blood-2006-03-010181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Mattar CN, Nathwani AC, Waddington SN, Dighe N, Kaeppel C, Nowrouzi A, McIntosh J, Johana NB, Ogden B, Fisk NM, Davidoff AM, David A, Peebles D, Valentine MB, Appelt JU, von Kalle C, Schmidt M, Biswas A, Choolani M, Chan JK (2011) Stable human FIX expression after 0.9G intrauterine gene transfer of self-complementary adeno-associated viral vector 5 and 8 in macaques. Mol Ther 19(11):1950–1960. https://doi.org/10.1038/mt.2011.107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Mattar CNZ, Gil-Farina I, Rosales C, Johana N, Tan YYW, McIntosh J, Kaeppel C, Waddington SN, Biswas A, Choolani M, Schmidt M, Nathwani AC, Chan JKY (2017) In utero transfer of adeno-associated viral vectors produces long-term factor IX levels in a cynomolgus macaque model. Mol Ther 25(8):1843–1853. https://doi.org/10.1016/j.ymthe.2017.04.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Greig JA, Nordin JM, Bote E, Makaron L, Garnett ME, Kattenhorn LM, Bell P, Goode T, Wilson JM (2016) Impact of intravenous infusion time on AAV8 vector pharmacokinetics, safety, and liver transduction in cynomolgus macaques. Mol Ther Methods Clin Dev 3(Suppl C):16079. https://doi.org/10.1038/mtm.2016.79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. D’Avola D, Lopez-Franco E, Sangro B, Paneda A, Grossios N, Gil-Farina I, Benito A, Twisk J, Paz M, Ruiz J, Schmidt M, Petry H, Harper P, de Salamanca RE, Fontanellas A, Prieto J, Gonzalez-Aseguinolaza G (2016) Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria. J Hepatol 65(4):776–783. https://doi.org/10.1016/j.jhep.2016.05.012

    Article  CAS  PubMed  Google Scholar 

  123. Bell P, Wang L, Gao G, Haskins ME, Tarantal AF, McCarter RJ, Zhu Y, Yu H, Wilson JM (2011) Inverse zonation of hepatocyte transduction with AAV vectors between mice and non-human primates. Mol Genet Metab 104(3):395–403. https://doi.org/10.1016/j.ymgme.2011.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Markusic DM, Nichols TC, Merricks EP, Palaschak B, Zolotukhin I, Marsic D, Zolotukhin S, Srivastava A, Herzog RW (2017) Evaluation of engineered AAV capsids for hepatic factor IX gene transfer in murine and canine models. J Transl Med 15(1):94. https://doi.org/10.1186/s12967-017-1200-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Rapti K, Louis-Jeune V, Kohlbrenner E, Ishikawa K, Ladage D, Hajjar RJ, Weber T (2012) Neutralizing antibodies against AAV serotypes 1, 2, 6 and 9 in sera of commonly used animal models and their significance for in vivo experiments. Mol Ther 20:S62–S62

    Article  Google Scholar 

  126. Calcedo R, Franco J, Qin Q, Richardson DW, Mason JB, Boyd S, Wilson JM (2015) Preexisting neutralizing antibodies to adeno-associated virus capsids in large animals other than monkeys may confound in vivo gene therapy studies. Hum Gene Ther Methods 26(3):103–105. https://doi.org/10.1089/hgtb.2015.082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Cao O, Dobrzynski E, Wang L, Nayak S, Mingle B, Terhorst C, Herzog RW (2007) Induction and role of regulatory CD4+CD25+ T cells in tolerance to the transgene product following hepatic in vivo gene transfer. Blood 110(4):1132–1140. https://doi.org/10.1182/blood-2007-02-073304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Hoffman BE, Martino AT, Sack BK, Cao O, Liao G, Terhorst C, Herzog RW (2011) Nonredundant roles of IL-10 and TGF-beta in suppression of immune responses to hepatic AAV-factor IX gene transfer. Mol Ther 19(7):1263–1272. https://doi.org/10.1038/mt.2011.33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Li H, Haurigot V, Doyon Y, Li T, Wong SY, Bhagwat AS, Malani N, Anguela XM, Sharma R, Ivanciu L, Murphy SL, Finn JD, Khazi FR, Zhou S, Paschon DE, Rebar EJ, Bushman FD, Gregory PD, Holmes MC, High KA (2011) In vivo genome editing restores haemostasis in a mouse model of haemophilia. Nature 475(7355):217–221. https://doi.org/10.1038/nature10177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Sharma R, Anguela XM, Doyon Y, Wechsler T, DeKelver RC, Sproul S, Paschon DE, Miller JC, Davidson RJ, Shivak D, Zhou S, Rieders J, Gregory PD, Holmes MC, Rebar EJ, High KA (2015) In vivo genome editing of the albumin locus as a platform for protein replacement therapy. Blood 126(15):1777–1784. https://doi.org/10.1182/blood-2014-12-615492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ran FA, Cong L, Yan WX, Scott DA, Gootenberg JS, Kriz AJ, Zetsche B, Shalem O, Wu X, Makarova KS, Koonin EV, Sharp PA, Zhang F (2015) In vivo genome editing using Staphylococcus aureus Cas9. Nature 520(7546):186–191. https://doi.org/10.1038/nature14299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Yang Y, Wang L, Bell P, McMenamin D, He Z, White J, Yu H, Xu C, Morizono H, Musunuru K, Batshaw ML, Wilson JM (2016) A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice. Nat Biotechnol 34(3):334–338. https://doi.org/10.1038/nbt.3469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Barzel A, Paulk NK, Shi Y, Huang Y, Chu K, Zhang F, Valdmanis PN, Spector LP, Porteus MH, Gaensler KM, Kay MA (2015) Promoterless gene targeting without nucleases ameliorates haemophilia B in mice. Nature 517(7534):360–364. https://doi.org/10.1038/nature13864

    Article  CAS  PubMed  Google Scholar 

  134. Markusic DM, Hoffman BE, Perrin GQ, Nayak S, Wang X, LoDuca PA, High KA, Herzog RW (2013) Effective gene therapy for haemophilic mice with pathogenic factor IX antibodies. EMBO Mol Med 5(11):1698–1709. https://doi.org/10.1002/emmm.201302859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Doerfler PA, Todd AG, Clement N, Falk DJ, Nayak S, Herzog RW, Byrne BJ (2016) Copackaged AAV9 vectors promote simultaneous immune tolerance and phenotypic correction of pompe disease. Hum Gene Ther 27(1):43–59. https://doi.org/10.1089/hum.2015.103

    Article  CAS  PubMed  Google Scholar 

  136. Han SO, Ronzitti G, Arnson B, Leborgne C, Li S, Mingozzi F, Koeberl D (2017) Low-dose liver-targeted gene therapy for pompe disease enhances therapeutic efficacy of ERT via immune tolerance induction. Mol Ther Methods Clin Dev 4:126–136. https://doi.org/10.1016/j.omtm.2016.12.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Crudele JM, Finn JD, Siner JI, Martin NB, Niemeyer GP, Zhou S, Mingozzi F, Lothrop CD Jr, Arruda VR (2015) AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice. Blood 125(10):1553–1561. https://doi.org/10.1182/blood-2014-07-588194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Wasserfall CH, Herzog RW (2009) Gene therapy approaches to induce tolerance in autoimmunity by reshaping the immune system. Curr Opin Investig Drugs 10(11):1143–1150

    CAS  PubMed  Google Scholar 

  139. Keeler GD, Kumar S, Palaschak B, Silverberg EL, Markusic DM, Jones NT, Hoffman BE (2018) Gene therapy-induced antigen-specific tregs inhibit neuro-inflammation and reverse disease in a mouse model of multiple sclerosis. Mol Ther 26(1):173–183. https://doi.org/10.1016/j.ymthe.2017.09.001

    Article  CAS  PubMed  Google Scholar 

  140. McIntosh JH, Cochrane M, Cobbold S, Waldmann H, Nathwani SA, Davidoff AM, Nathwani AC (2012) Successful attenuation of humoral immunity to viral capsid and transgenic protein following AAV-mediated gene transfer with a non-depleting CD4 antibody and cyclosporine. Gene Ther 19(1):78–85. https://doi.org/10.1038/gt.2011.64

    Article  CAS  PubMed  Google Scholar 

  141. Corti M, Elder ME, Falk DJ, Lawson L, Smith BK, Nayak S, Conlon TJ, Clement N, Erger K, Lavassani E, Green MM, Doerfler PA, Herzog RW, Byrne BJ (2014) B-cell depletion is protective against anti-AAV capsid immune response: a human subject case study. Mol Ther Methods Clin Dev 1. https://doi.org/10.1038/mtm.2014.33

    Article  Google Scholar 

  142. Scallan CD, Jiang H, Liu T, Patarroyo-White S, Sommer JM, Zhou S, Couto LB, Pierce GF (2006) Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice. Blood 107(5):1810–1817. https://doi.org/10.1182/blood-2005-08-3229

    Article  CAS  PubMed  Google Scholar 

  143. Calcedo R, Vandenberghe LH, Gao G, Lin J, Wilson JM (2009) Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis 199(3):381–390. https://doi.org/10.1086/595830

    Article  PubMed  Google Scholar 

  144. Wang L, Calcedo R, Wang H, Bell P, Grant R, Vandenberghe LH, Sanmiguel J, Morizono H, Batshaw ML, Wilson JM (2010) The pleiotropic effects of natural AAV infections on liver-directed gene transfer in macaques. Mol Ther 18(1):126–134. https://doi.org/10.1038/mt.2009.245

    Article  CAS  PubMed  Google Scholar 

  145. Mingozzi F, Anguela XM, Pavani G, Chen Y, Davidson RJ, Hui DJ, Yazicioglu M, Elkouby L, Hinderer CJ, Faella A, Howard C, Tai A, Podsakoff GM, Zhou S, Basner-Tschakarjan E, Wright JF, High KA (2013) Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci Transl Med 5(194):194ra192. https://doi.org/10.1126/scitranslmed.3005795

    Article  CAS  Google Scholar 

  146. Meliani A, Boisgerault F, Fitzpatrick Z, Marmier S, Leborgne C, Collaud F, Simon Sola M, Charles S, Ronzitti G, Vignaud A, van Wittenberghe L, Marolleau B, Jouen F, Tan S, Boyer O, Christophe O, Brisson AR, Maguire CA, Mingozzi F (2017) Enhanced liver gene transfer and evasion of preexisting humoral immunity with exosome-enveloped AAV vectors. Blood Adv 1(23):2019–2031. https://doi.org/10.1182/bloodadvances.2017010181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Mimuro J, Mizukami H, Hishikawa S, Ikemoto T, Ishiwata A, Sakata A, Ohmori T, Madoiwa S, Ono F, Ozawa K, Sakata Y (2013) Minimizing the inhibitory effect of neutralizing antibody for efficient gene expression in the liver with adeno-associated virus 8 vectors. Mol Ther 21(2):318–323. https://doi.org/10.1038/mt.2012.258

    Article  CAS  PubMed  Google Scholar 

  148. Burton M, Nakai H, Colosi P, Cunningham J, Mitchell R, Couto L (1999) Coexpression of factor VIII heavy and light chain adeno-associated viral vectors produces biologically active protein. Proc Natl Acad Sci U S A 96(22):12725–12730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Duan D, Yue Y, Engelhardt JF (2001) Expanding AAV packaging capacity with trans-splicing or overlapping vectors: a quantitative comparison. Mol Ther 4(4):383–391. https://doi.org/10.1006/mthe.2001.0456

    Article  CAS  PubMed  Google Scholar 

  150. Nakai H, Iwaki Y, Kay MA, Couto LB (1999) Isolation of recombinant adeno-associated virus vector-cellular DNA junctions from mouse liver. J Virol 73(7):5438–5447

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Nakai H, Montini E, Fuess S, Storm TA, Grompe M, Kay MA (2003) AAV serotype 2 vectors preferentially integrate into active genes in mice. Nat Genet 34(3):297–302. https://doi.org/10.1038/ng1179

    Article  CAS  PubMed  Google Scholar 

  152. Moscioni D, Morizono H, McCarter RJ, Stern A, Cabrera-Luque J, Hoang A, Sanmiguel J, Wu D, Bell P, Gao GP, Raper SE, Wilson JM, Batshaw ML (2006) Long-term correction of ammonia metabolism and prolonged survival in ornithine transcarbamylase-deficient mice following liver-directed treatment with adeno-associated viral vectors. Mol Ther 14(1):25–33. https://doi.org/10.1016/j.ymthe.2006.03.009

    Article  CAS  PubMed  Google Scholar 

  153. Bell P, Wang L, Lebherz C, Flieder DB, Bove MS, Wu D, Gao GP, Wilson JM, Wivel NA (2005) No evidence for tumorigenesis of AAV vectors in a large-scale study in mice. Mol Ther 12(2):299–306. https://doi.org/10.1016/j.ymthe.2005.03.020

    Article  CAS  PubMed  Google Scholar 

  154. Li H, Malani N, Hamilton SR, Schlachterman A, Bussadori G, Edmonson SE, Shah R, Arruda VR, Mingozzi F, Wright JF, Bushman FD, High KA (2011) Assessing the potential for AAV vector genotoxicity in a murine model. Blood 117(12):3311–3319. https://doi.org/10.1182/blood-2010-08-302729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Nathwani AC, Rosales C, McIntosh J, Rastegarlari G, Nathwani D, Raj D, Nawathe S, Waddington SN, Bronson R, Jackson S, Donahue RE, High KA, Mingozzi F, Ng CY, Zhou J, Spence Y, McCarville MB, Valentine M, Allay J, Coleman J, Sleep S, Gray JT, Nienhuis AW, Davidoff AM (2011) Long-term safety and efficacy following systemic administration of a self-complementary AAV vector encoding human FIX pseudotyped with serotype 5 and 8 capsid proteins. Mol Ther 19(5):876–885. https://doi.org/10.1038/mt.2010.274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Chandler RJ, LaFave MC, Varshney GK, Trivedi NS, Carrillo-Carrasco N, Senac JS, Wu W, Hoffmann V, Elkahloun AG, Burgess SM, Venditti CP (2015) Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J Clin Invest 125(2):870–880. https://doi.org/10.1172/JCI79213

    Article  PubMed  PubMed Central  Google Scholar 

  157. Chandler RJ, Sands MS, Venditti CP (2017) Recombinant adeno-associated viral integration and genotoxicity: insights from animal models. Hum Gene Ther 28(4):314–322. https://doi.org/10.1089/hum.2017.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Gil-Farina I, Fronza R, Kaeppel C, Lopez-Franco E, Ferreira V, D’Avola D, Benito A, Prieto J, Petry H, Gonzalez-Aseguinolaza G, Schmidt M (2016) Recombinant AAV integration is not associated with hepatic genotoxicity in nonhuman primates and patients. Mol Ther 24(6):1100–1105. https://doi.org/10.1038/mt.2016.52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Nault JC, Datta S, Imbeaud S, Franconi A, Mallet M, Couchy G, Letouze E, Pilati C, Verret B, Blanc JF, Balabaud C, Calderaro J, Laurent A, Letexier M, Bioulac-Sage P, Calvo F, Zucman-Rossi J (2015) Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet 47(10):1187–1193. https://doi.org/10.1038/ng.3389

    Article  CAS  PubMed  Google Scholar 

  160. Nault JC, Mami I, La Bella T, Datta S, Imbeaud S, Franconi A, Mallet M, Couchy G, Letouze E, Pilati C, Verret B, Blanc JF, Balabaud C, Calderaro J, Laurent A, Letexier M, Bioulac-Sage P, Calvo F, Zucman-Rossi J (2016) Wild-type AAV insertions in hepatocellular carcinoma do not inform debate over genotoxicity risk of vectorized AAV. Mol Ther 24(4):660–661. https://doi.org/10.1038/mt.2016.47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of Florida, Gainesville, FL, USA

    Brett Palaschak & Roland W. Herzog

  2. Department of Pediatrics, Indiana University, Indianapolis, IN, USA

    Roland W. Herzog & David M. Markusic

Authors
  1. Brett Palaschak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roland W. Herzog
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David M. Markusic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David M. Markusic .

Editor information

Editors and Affiliations

  1. Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA

    Michael J. Castle

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Palaschak, B., Herzog, R.W., Markusic, D.M. (2019). AAV-Mediated Gene Delivery to the Liver: Overview of Current Technologies and Methods. In: Castle, M. (eds) Adeno-Associated Virus Vectors. Methods in Molecular Biology, vol 1950. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-9139-6_20

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-9139-6_20

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-9138-9

  • Online ISBN: 978-1-4939-9139-6

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation