Gene Therapy in Pediatric Liver Disease

  • Andrès F. MuroEmail author
  • Lorenzo D’Antiga
  • Federico MingozziEmail author


The liver is an attractive organ for the development of gene-based therapeutic approaches. In the recent years, gene therapy for monogenic diseases of the liver using recombinant adeno-associated virus (rAAV) has shown safety and in some cases efficacy in clinical trials in adult subjects with hemophilia A and B and acute intermittent porphyria. Multi-year expression of the transgenes has been documented, making liver gene therapy a promising curative treatment. The success is consequent to more than two decades of experimentation in small- and large-animal models and humans. This work allowed investigators to understand and overcome some of the major immunological hurdles, such as humoral and cellular responses to the vector. However, due to the loss of viral DNA during hepatocyte proliferation, AAV vector-mediated liver gene transfer is predicted to be less durable in neonatal and pediatric subjects. Modulation of the antibody response against the viral capsid is being explored to allow for readministration of the vector. Alternatively, the permanent modification of the hepatocyte genome in vivo could overcome this limitation.

This chapter focuses on different gene therapy approaches that can be applied to cure monogenic liver diseases. The basic concepts of gene replacement therapy are presented. Key experiments in animal models, as well as innovative approaches based in the use of engineered endonucleases to modify permanently the hepatocyte genome are discussed.


  1. 1.
    Blaese RM, Culver KW, Miller AD, Carter CS, Fleisher T, Clerici M, et al. T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Science. 1995;270(5235):475–80.PubMedCrossRefGoogle Scholar
  2. 2.
    Bordignon C, Notarangelo LD, Nobili N, Ferrari G, Casorati G, Panina P, et al. Gene therapy in peripheral blood lymphocytes and bone marrow for ADA- immunodeficient patients. Science. 1995;270(5235):470–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao GP, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab. 2003;80(1–2):148–58.PubMedCrossRefGoogle Scholar
  4. 4.
    Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science. 2000;288(5466):669–72.PubMedCrossRefGoogle Scholar
  5. 5.
    Hacein-Bey-Abina S, von Kalle C, Schmidt M, Le Deist F, Wulffraat N, McIntyre E, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med. 2003;348(3):255–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Mukherjee S, Thrasher AJ. Gene therapy for PIDs: progress, pitfalls and prospects. Gene. 2013;525(2):174–81.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Mingozzi F, High KA. Immune responses to AAV in clinical trials. Curr Gene Ther. 2007;7(5):316–24.PubMedCrossRefGoogle Scholar
  8. 8.
    Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849–60.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med. 2008;358(21):2231–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med. 2008;358(21):2240–8.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009;326(5954):818–23.PubMedCrossRefGoogle Scholar
  12. 12.
    Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013;341(6148):1233158.PubMedCrossRefGoogle Scholar
  13. 13.
    Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014;371(21):1994–2004.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    George LA, Sullivan SK, Giermasz A, Rasko JEJ, Samelson-Jones BJ, Ducore J, et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med. 2017;377(23):2215–27.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Fagiuoli S, Daina E, D’Antiga L, Colledan M, Remuzzi G. Monogenic diseases that can be cured by liver transplantation. J Hepatol. 2013;59(3):595–612.CrossRefPubMedGoogle Scholar
  17. 17.
    Lachmann RH. Enzyme replacement therapy for lysosomal storage diseases. Curr Opin Pediatr. 2011;23(6):588–93.PubMedCrossRefGoogle Scholar
  18. 18.
    D’Antiga L, Colledan M. Surgical gene therapy by domino auxiliary liver transplantation. Liver Transplant. 2015;21(11):1338–9.CrossRefGoogle Scholar
  19. 19.
    Kasahara M, Sakamoto S, Horikawa R, Koji U, Mizuta K, Shinkai M, et al. Living donor liver transplantation for pediatric patients with metabolic disorders: the Japanese multicenter registry. Pediatr Transplant. 2014;18(1):6–15.PubMedCrossRefGoogle Scholar
  20. 20.
    Vara R, Turner C, Mundy H, Heaton ND, Rela M, Mieli-Vergani G, et al. Liver transplantation for propionic acidemia in children. Liver Transplant. 2011;17(6):661–7.CrossRefGoogle Scholar
  21. 21.
    Wang L, Wang H, Bell P, McMenamin D, Wilson JM. Hepatic gene transfer in neonatal mice by adeno-associated virus serotype 8 vector. Hum Gene Ther. 2012;23(5):533–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Bortolussi G, Zentilin L, Vanikova J, Bockor L, Bellarosa C, Mancarella A, et al. Life-long correction of hyperbilirubinemia with a neonatal liver-specific AAV-mediated gene transfer in a lethal mouse model of Crigler Najjar syndrome. Hum Gene Ther. 2014;25(9):844–55.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Cunningham SC, Dane AP, Spinoulas A, Logan GJ, Alexander IE. Gene delivery to the juvenile mouse liver using AAV2/8 vectors. Mol Ther. 2008;16(6):1081–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Coppoletta JM, Wolbach SB. Body length and organ weights of infants and children: a study of the body length and normal weights of the more important vital organs of the body between birth and twelve years of age. Am J Pathol. 1933;9(1):55–70.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Garby L, Lammert O, Kock KF, Thobo-Carlsen B. Weights of brain, heart, liver, kidneys, and spleen in healthy and apparently healthy adult Danish subjects. Am J Hum Biol. 1993;5(3):291–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Hansen K, Horslen S. Metabolic liver disease in children. Liver Transplant. 2008;14(4):391–411.CrossRefGoogle Scholar
  27. 27.
    Junge N, Mingozzi F, Ott M, Baumann U. Adeno-associated virus vector-based gene therapy for monogenetic metabolic diseases of the liver. J Pediatr Gastroenterol Nutr. 2015;60(4):433–40.PubMedCrossRefGoogle Scholar
  28. 28.
    Kay MA, Glorioso JC, Naldini L. Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics. Nat Med. 2001;7(1):33–40.PubMedCrossRefGoogle Scholar
  29. 29.
    Hardee CL, Arevalo-Soliz LM, Hornstein BD, Zechiedrich L. Advances in non-viral DNA vectors for gene therapy. Genes. 2017;8(2):65.PubMedCentralCrossRefGoogle Scholar
  30. 30.
    Miller DG, Adam MA, Miller AD. Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection. Mol Cell Biol. 1990;10(8):4239–42.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Hacein-Bey-Abina S, Garrigue A, Wang GP, Soulier J, Lim A, Morillon E, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest. 2008;118(9):3132–42.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003;302(5644):415–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Ribeil JA, Hacein-Bey-Abina S, Payen E, Magnani A, Semeraro M, Magrin E, et al. Gene therapy in a patient with sickle cell disease. N Engl J Med. 2017;376(9):848–55.PubMedCrossRefGoogle Scholar
  34. 34.
    Suzuki Y, Craigie R. The road to chromatin—nuclear entry of retroviruses. Nat Rev Microbiol. 2007;5(3):187–96.PubMedCrossRefGoogle Scholar
  35. 35.
    Naldini L. Ex vivo gene transfer and correction for cell-based therapies. Nat Rev Genet. 2011;12(5):301–15.PubMedCrossRefGoogle Scholar
  36. 36.
    Kotterman MA, Chalberg TW, Schaffer DV. Viral vectors for gene therapy: translational and clinical outlook. Annu Rev Biomed Eng. 2015;17:63–89.PubMedCrossRefGoogle Scholar
  37. 37.
    Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013;341(6148):1233151.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, et al. Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature. 2010;467(7313):318–22.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Campochiaro PA, Lauer AK, Sohn EH, Mir TA, Naylor S, Anderton MC, et al. Lentiviral vector gene transfer of endostatin/angiostatin for macular degeneration (GEM) study. Hum Gene Ther. 2017;28(1):99–111.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Dalkara D, Goureau O, Marazova K, Sahel JA. Let there be light: gene and Cell therapy for blindness. Hum Gene Ther. 2016;27(2):134–47.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Palfi S, Gurruchaga JM, Ralph GS, Lepetit H, Lavisse S, Buttery PC, et al. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: a dose escalation, open-label, phase 1/2 trial. Lancet. 2014;383(9923):1138–46.PubMedCrossRefGoogle Scholar
  42. 42.
    Cantore A, Annoni A, Lui T, Bartolaccini S, Biffi M, Russo F, et al. Liver-directed gene therapy for hemophilia B with immune stealth lentiviral vectors. Blood. 2017;130(Suppl 1):605.Google Scholar
  43. 43.
    Cantore A, Ranzani M, Bartholomae CC, Volpin M, Valle PD, Sanvito F, et al. Liver-directed lentiviral gene therapy in a dog model of hemophilia B. Sci Transl Med. 2015;7(277):277ra28.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Milani M, Annoni A, Bartolaccini S, Biffi M, Russo F, Di Tomaso T, et al. Genome editing for scalable production of alloantigen-free lentiviral vectors for in vivo gene therapy. EMBO Mol Med. 2017;9(11):1558–73.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Cotmore SF, Tattersall P. Parvoviruses: small does not mean simple. Annu Rev Virol. 2014;1(1):517–37.PubMedCrossRefGoogle Scholar
  46. 46.
    Niemeyer GP, Herzog RW, Mount J, Arruda VR, Tillson DM, Hathcock J, et al. Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy. Blood. 2009;113(4):797–806.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Buchlis G, Podsakoff GM, Radu A, Hawk SM, Flake AW, Mingozzi F, et al. Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer. Blood. 2012;119(13):3038–41.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Smith RH. Adeno-associated virus integration: virus versus vector. Gene Ther. 2008;15(11):817–22.PubMedCrossRefGoogle Scholar
  49. 49.
    Kaeppel C, Beattie SG, Fronza R, van Logtenstein R, Salmon F, Schmidt S, et al. A largely random AAV integration profile after LPLD gene therapy. Nat Med. 2013;19(7):889–91.PubMedCrossRefGoogle Scholar
  50. 50.
    Nakai H, Wu X, Fuess S, Storm TA, Munroe D, Montini E, et al. Large-scale molecular characterization of adeno-associated virus vector integration in mouse liver. J Virol. 2005;79(6):3606–14.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Donsante A, Miller DG, Li Y, Vogler C, Brunt EM, Russell DW, et al. AAV vector integration sites in mouse hepatocellular carcinoma. Science. 2007;317(5837):477.PubMedCrossRefGoogle Scholar
  52. 52.
    Li H, Malani N, Hamilton SR, Schlachterman A, Bussadori G, Edmonson SE, et al. Assessing the potential for AAV vector genotoxicity in a murine model. Blood. 2011;117(12):3311–9.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Chandler RJ, LaFave MC, Varshney GK, Trivedi NS, Carrillo-Carrasco N, Senac JS, et al. Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J Clin Invest. 2015;125(2):870–80.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Chandler RJ, LaFave MC, Varshney GK, Burgess SM, Venditti CP. Genotoxicity in mice following AAV gene delivery: a safety concern for human gene therapy? Mol Ther. 2016;24(2):198–201.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Nathwani AC, Rosales C, McIntosh J, Rastegarlari G, Nathwani D, Raj D, et al. 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. 2011;19(5):876–85.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Nault JC, Datta S, Imbeaud S, Franconi A, Mallet M, Couchy G, et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet. 2015;47(10):1187–93.PubMedCrossRefGoogle Scholar
  57. 57.
    Asokan A, Schaffer DV, Samulski RJ. The AAV vector toolkit: poised at the clinical crossroads. Mol Ther. 2012;20(4):699–708.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    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.PubMedCrossRefGoogle Scholar
  59. 59.
    Wu Z, Asokan A, Samulski RJ. Adeno-associated virus serotypes: vector toolkit for human gene therapy. Mol Ther. 2006;14(3):316–27.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Pillay S, Meyer NL, Puschnik AS, Davulcu O, Diep J, Ishikawa Y, et al. An essential receptor for adeno-associated virus infection. Nature. 2016;530(7588):108–12.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Hastie E, Samulski RJ. Recombinant adeno-associated virus vectors in the treatment of rare diseases. Expert Opin Orphan Drugs. 2015;3(6):675–89.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    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.PubMedCrossRefGoogle Scholar
  63. 63.
    Colella P, Ronzitti G, Mingozzi F. Emerging issues in AAV-mediated in vivo gene therapy. Mol Ther Methods Clin Dev. 2018;8:87–104.PubMedCrossRefGoogle Scholar
  64. 64.
    Mingozzi F, High KA. Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood. 2013;122(1):23–36.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Dong JY, Fan PD, Frizzell RA. Quantitative analysis of the packaging capacity of recombinant adeno-associated virus. Hum Gene Ther. 1996;7(17):2101–12.PubMedCrossRefGoogle Scholar
  66. 66.
    Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci U S A. 2008;105(33):11915–20.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR, Sutherland JE, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet. 2014;383(9911):60–8.PubMedCrossRefGoogle Scholar
  68. 68.
    Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med. 2017;376(1):41–51.PubMedCrossRefGoogle Scholar
  69. 69.
    Guo S, Booten SL, Aghajan M, Hung G, Zhao C, Blomenkamp K, et al. Antisense oligonucleotide treatment ameliorates alpha-1 antitrypsin-related liver disease in mice. J Clin Invest. 2014;124(1):251–61.PubMedCrossRefGoogle Scholar
  70. 70.
    Rangaranjan S, Walsh L, Lester W, Perry D, Madan B, Laffan M, et al. AAV5-factor VIII gene transfer in severe hemophilia A. N Engl J Med. 2017;377:2519–30.CrossRefGoogle Scholar
  71. 71.
    D’Avola D, Lopez-Franco E, Sangro B, Paneda A, Grossios N, Gil-Farina I, et al. Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria. J Hepatol. 2016;65(4):776–83.PubMedCrossRefGoogle Scholar
  72. 72.
    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.PubMedCrossRefGoogle Scholar
  73. 73.
    Miesbach W, Meijer K, Coppens M, Kampmann P, Klamroth R, Schutgens R, et al. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood. 2018;131(9):1022–31.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Mannucci PM, Tuddenham EG. The hemophilias—from royal genes to gene therapy. N Engl J Med. 2001;344(23):1773–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Soucie JM, Nuss R, Evatt B, Abdelhak A, Cowan L, Hill H, et al. Mortality among males with hemophilia: relations with source of medical care. The Hemophilia Surveillance System Project Investigators. Blood. 2000;96(2):437–42.PubMedGoogle Scholar
  76. 76.
    White GC 2nd, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J, et al. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 2001;85(3):560.PubMedCrossRefGoogle Scholar
  77. 77.
    Rangarajan S, Walsh L, Lester W, Perry D, Madan B, Laffan M, et al. AAV5-factor VIII gene transfer in severe hemophilia A. N Engl J Med. 2017;377(26):2519–30.PubMedCrossRefGoogle Scholar
  78. 78.
    Jiang H, Pierce GF, Ozelo MC, de Paula EV, Vargas JA, Smith P, et al. Evidence of multiyear factor IX expression by AAV-mediated gene transfer to skeletal muscle in an individual with severe hemophilia B. Mol Ther. 2006;14(3):452–5.PubMedCrossRefGoogle Scholar
  79. 79.
    Mount JD, Herzog RW, Tillson DM, Goodman SA, Robinson N, McCleland ML, et al. Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy. Blood. 2002;99(8):2670–6.PubMedCrossRefGoogle Scholar
  80. 80.
    Sabatino DE, Armstrong E, Edmonson S, Liu YL, Pleimes M, Schuettrumpf J, et al. Novel hemophilia B mouse models exhibiting a range of mutations in the factor IX gene. Blood. 2004;104(9):2767–74.PubMedCrossRefGoogle Scholar
  81. 81.
    Arruda VR. Toward gene therapy for hemophilia A with novel adenoviral vectors: successes and limitations in canine models. J Thromb Haemost. 2006;4(6):1215–7.PubMedCrossRefGoogle Scholar
  82. 82.
    Sabatino DE, Nichols TC, Merricks E, Bellinger DA, Herzog RW, Monahan PE. Animal models of hemophilia. Prog Mol Biol Transl Sci. 2012;105:151–209.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Arruda VR, Doshi BS, Samelson-Jones BJ. Novel approaches to hemophilia therapy: successes and challenges. Blood. 2017;130(21):2251–6.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Crudele JM, Finn JD, Siner JI, Martin NB, Niemeyer GP, Zhou S, et al. AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice. Blood. 2015;125(10):1553–61.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Finn JD, Nichols TC, Svoronos N, Merricks EP, Bellenger DA, Zhou S, et al. The efficacy and the risk of immunogenicity of FIX Padua (R338L) in hemophilia B dogs treated by AAV muscle gene therapy. Blood. 2012;120(23):4521–3.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Cantore A, Nair N, Della Valle P, Di Matteo M, Matrai J, Sanvito F, et al. Hyperfunctional coagulation factor IX improves the efficacy of gene therapy in hemophilic mice. Blood. 2012;120(23):4517–20.PubMedCrossRefGoogle Scholar
  87. 87.
    Monahan PE, Sun J, Gui T, Hu G, Hannah WB, Wichlan DG, et al. Employing a gain-of-function factor IX variant R338L to advance the efficacy and safety of hemophilia B human gene therapy: preclinical evaluation supporting an ongoing adeno-associated virus clinical trial. Hum Gene Ther. 2015;26(2):69–81.PubMedCrossRefGoogle Scholar
  88. 88.
    Graham T, McIntosh J, Work LM, Nathwani A, Baker AH. Performance of AAV8 vectors expressing human factor IX from a hepatic-selective promoter following intravenous injection into rats. Genet Vaccines Ther. 2008;6:9.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Nathwani AC, Gray JT, McIntosh J, Ng CY, Zhou J, Spence Y, et al. 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. 2007;109(4):1414–21.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Nathwani AC, Gray JT, Ng CY, Zhou J, Spence Y, Waddington SN, et al. 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. 2006;107(7):2653–61.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Vercauteren K, Hoffman BE, Zolotukhin I, Keeler GD, Xiao JW, Basner-Tschakarjan E, et al. Superior in vivo transduction of human hepatocytes using engineered AAV3 capsid. Mol Ther. 2016;24(6):1042–9.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Crigler JF Jr, Najjar VA. Congenital familial nonhemolytic jaundice with kernicterus. Pediatrics. 1952;10(2):169–80.PubMedGoogle Scholar
  93. 93.
    Strauss KA, Robinson DL, Vreman HJ, Puffenberger EG, Hart G, Morton DH. Management of hyperbilirubinemia and prevention of kernicterus in 20 patients with Crigler-Najjar disease. Eur J Pediatr. 2006;165(5):306–19.PubMedCrossRefGoogle Scholar
  94. 94.
    Cornelius CE, Arias IM. Animal model of human disease. Crigler-Najjar syndrome. Animal model: hereditary nonhemolytic unconjugated hyperbilirubinemia in Gunn rats. Am J Pathol. 1972;69(2):369–72.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Iyanagi T, Emi Y, Ikushiro S. Biochemical and molecular aspects of genetic disorders of bilirubin metabolism. Biochim Biophys Acta. 1998;1407(3):173–84.PubMedCrossRefGoogle Scholar
  96. 96.
    Miranda PS, Bosma PJ. Towards liver-directed gene therapy for Crigler-Najjar syndrome. Curr Gene Ther. 2009;9(2):72–82.PubMedCrossRefGoogle Scholar
  97. 97.
    Seppen J, Bakker C, de Jong B, Kunne C, van den Oever K, Vandenberghe K, et al. Adeno-associated virus vector serotypes mediate sustained correction of bilirubin UDP glucuronosyltransferase deficiency in rats. Mol Ther. 2006;13(6):1085–92.PubMedCrossRefGoogle Scholar
  98. 98.
    Montenegro-Miranda PS, Pichard V, Aubert D, Ten Bloemendaal L, Duijst S, de Waart DR, et al. In the rat liver, adenoviral gene transfer efficiency is comparable to AAV. Gene Ther. 2014;21(2):168–74.PubMedCrossRefGoogle Scholar
  99. 99.
    Kren BT, Parashar B, Bandyopadhyay P, Chowdhury NR, Chowdhury JR, Steer CJ. Correction of the UDP-glucuronosyltransferase gene defect in the gunn rat model of Crigler-Najjar syndrome type I with a chimeric oligonucleotide. Proc Natl Acad Sci U S A. 1999;96(18):10349–54.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Ronzitti G, Bortolussi G, van Dijk R, Collaud F, Charles S, Leborgne C, et al. A translationally optimized AAV-UGT1A1 vector drives safe and long-lasting correction of Crigler-Najjar syndrome. Mol Ther Methods Clin Dev. 2016;3:16049.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Fox IJ, Chowdhury JR, Kaufman SS, Goertzen TC, Chowdhury NR, Warkentin PI, et al. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med. 1998;338(20):1422–6.PubMedCrossRefGoogle Scholar
  102. 102.
    Sneitz N, Bakker CT, de Knegt RJ, Halley DJ, Finel M, Bosma PJ. Crigler-Najjar syndrome in the Netherlands: identification of four novel UGT1A1 alleles, genotype-phenotype correlation, and functional analysis of 10 missense mutants. Hum Mutat. 2010;31(1):52–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Bortolussi G, Baj G, Vodret S, Viviani G, Bittolo T, Muro AF. Age-dependent pattern of cerebellar susceptibility to bilirubin neurotoxicity in vivo. Dis Model Mech. 2014;7(9):1057–68.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Bortolussi G, Zentilin L, Baj G, Giraudi P, Bellarosa C, Giacca M, et al. Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer. FASEB J. 2012;26(3):1052–63.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Bockor L, Bortolussi G, Iaconcig A, Chiaruttini G, Tiribelli C, Giacca M, et al. Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels of hUgt1a1 enzyme in a mouse model of Crigler-Najjar syndrome type I. Gene Ther. 2017;24(10):649–60.PubMedCrossRefGoogle Scholar
  106. 106.
    Fontanellas A, Avila MA, Berraondo P. Emerging therapies for acute intermittent porphyria. Expert Rev Mol Med. 2016;18:e17.PubMedCrossRefGoogle Scholar
  107. 107.
    Unzu C, Sampedro A, Mauleon I, Gonzalez-Aparicio M, Enriquez de Salamanca R, Prieto J, et al. Helper-dependent adenoviral liver gene therapy protects against induced attacks and corrects protein folding stress in acute intermittent porphyria mice. Hum Mol Genet. 2013;22(14):2929–40.PubMedCrossRefGoogle Scholar
  108. 108.
    Paneda A, Lopez-Franco E, Kaeppel C, Unzu C, Gil-Royo AG, D’Avola D, et al. Safety and liver transduction efficacy of rAAV5-cohPBGD in nonhuman primates: a potential therapy for acute intermittent porphyria. Hum Gene Ther. 2013;24(12):1007–17.PubMedCrossRefGoogle Scholar
  109. 109.
    Yasuda M, Bishop DF, Fowkes M, Cheng SH, Gan L, Desnick RJ. AAV8-mediated gene therapy prevents induced biochemical attacks of acute intermittent porphyria and improves neuromotor function. Mol Ther. 2010;18(1):17–22.PubMedCrossRefGoogle Scholar
  110. 110.
    Unzu C, Sampedro A, Mauleon I, Alegre M, Beattie SG, de Salamanca RE, et al. Sustained enzymatic correction by rAAV-mediated liver gene therapy protects against induced motor neuropathy in acute porphyria mice. Mol Ther. 2011;19(2):243–50.PubMedCrossRefGoogle Scholar
  111. 111.
    Soonawalla ZF, Orug T, Badminton MN, Elder GH, Rhodes JM, Bramhall SR, et al. Liver transplantation as a cure for acute intermittent porphyria. Lancet. 2004;363(9410):705–6.PubMedCrossRefGoogle Scholar
  112. 112.
    Singal AK, Parker C, Bowden C, Thapar M, Liu L, McGuire BM. Liver transplantation in the management of porphyria. Hepatology. 2014;60(3):1082–9.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Davidoff AM, Gray JT, Ng CY, Zhang Y, Zhou J, Spence Y, et al. 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. 2005;11(6):875–88.PubMedCrossRefGoogle Scholar
  114. 114.
    Hodges PE, Rosenberg LE. The spfash mouse: a missense mutation in the ornithine transcarbamylase gene also causes aberrant mRNA splicing. Proc Natl Acad Sci U S A. 1989;86(11):4142–6.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Kiwaki K, Kanegae Y, Saito I, Komaki S, Nakamura K, Miyazaki JI, et al. Correction of ornithine transcarbamylase deficiency in adult spf(ash) mice and in OTC-deficient human hepatocytes with recombinant adenoviruses bearing the CAG promoter. Hum Gene Ther. 1996;7(7):821–30.PubMedCrossRefGoogle Scholar
  116. 116.
    Ye X, Robinson MB, Batshaw ML, Furth EE, Smith I, Wilson JM. Prolonged metabolic correction in adult ornithine transcarbamylase-deficient mice with adenoviral vectors. J Biol Chem. 1996;271(7):3639–46.PubMedCrossRefGoogle Scholar
  117. 117.
    Ye X, Robinson MB, Pabin C, Quinn T, Jawad A, Wilson JM, et al. Adenovirus-mediated in vivo gene transfer rapidly protects ornithine transcarbamylase-deficient mice from an ammonium challenge. Pediatr Res. 1997;41(4 Pt 1):527–34.PubMedCrossRefGoogle Scholar
  118. 118.
    Batshaw ML, Robinson MB, Ye X, Pabin C, Daikhin Y, Burton BK, et al. Correction of ureagenesis after gene transfer in an animal model and after liver transplantation in humans with ornithine transcarbamylase deficiency. Pediatr Res. 1999;46(5):588–93.PubMedCrossRefGoogle Scholar
  119. 119.
    Raper SE, Wilson JM, Yudkoff M, Robinson MB, Ye X, Batshaw ML. Developing adenoviral-mediated in vivo gene therapy for ornithine transcarbamylase deficiency. J Inherit Metab Dis. 1998;21(Suppl 1):119–37.PubMedCrossRefGoogle Scholar
  120. 120.
    Zimmer KP, Bendiks M, Mori M, Kominami E, Robinson MB, Ye X, et al. Efficient mitochondrial import of newly synthesized ornithine transcarbamylase (OTC) and correction of secondary metabolic alterations in spf(ash) mice following gene therapy of OTC deficiency. Mol Med. 1999;5(4):244–53.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Raper SE, Yudkoff M, Chirmule N, Gao GP, Nunes F, Haskal ZJ, et al. A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency. Hum Gene Ther. 2002;13(1):163–75.PubMedCrossRefGoogle Scholar
  122. 122.
    Moscioni D, Morizono H, McCarter RJ, Stern A, Cabrera-Luque J, Hoang A, et al. 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. 2006;14(1):25–33.PubMedCrossRefGoogle Scholar
  123. 123.
    Cunningham SC, Spinoulas A, Carpenter KH, Wilcken B, Kuchel PW, Alexander IE. AAV2/8-mediated correction of OTC deficiency is robust in adult but not neonatal Spf(ash) mice. Mol Ther. 2009;17(8):1340–6.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Cunningham SC, Kok CY, Dane AP, Carpenter K, Kizana E, Kuchel PW, et al. Induction and prevention of severe hyperammonemia in the spfash mouse model of ornithine transcarbamylase deficiency using shRNA and rAAV-mediated gene delivery. Mol Ther. 2011;19(5):854–9.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Cunningham SC, Kok CY, Spinoulas A, Carpenter KH, Alexander IE. AAV-encoded OTC activity persisting to adulthood following delivery to newborn spf(ash) mice is insufficient to prevent shRNA-induced hyperammonaemia. Gene Ther. 2013;20(12):1184–7.PubMedCrossRefGoogle Scholar
  126. 126.
    Wang L, Wang H, Morizono H, Bell P, Jones D, Lin J, et al. Sustained correction of OTC deficiency in spf (ash) mice using optimized self-complementary AAV2/8 vectors. Gene Ther. 2012;19(4):404–10.PubMedCrossRefGoogle Scholar
  127. 127.
    Wang L, Morizono H, Lin J, Bell P, Jones D, McMenamin D, et al. Preclinical evaluation of a clinical candidate AAV8 vector for ornithine transcarbamylase (OTC) deficiency reveals functional enzyme from each persisting vector genome. Mol Genet Metab. 2012;105(2):203–11.PubMedCrossRefGoogle Scholar
  128. 128.
    Murillo-Sauca O, Moreno D, Gazquez C, Barberia M, Cenzano I, Solchaga SM, et al. Gene therapy optimization for Wilson’s disease. J Hepatol. 2018;68:S83.CrossRefGoogle Scholar
  129. 129.
    McIntosh J, Lenting PJ, Rosales C, Lee D, Rabbanian S, Raj D, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Puzzo F, Colella P, Biferi MG, Bali D, Paulk NK, Vidal P, et al. Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid alpha-glucosidase. Sci Transl Med. 2017;9(418).Google Scholar
  131. 131.
    Ferla R, Claudiani P, Cotugno G, Saccone P, De Leonibus E, Auricchio A. Similar therapeutic efficacy between a single administration of gene therapy and multiple administrations of recombinant enzyme in a mouse model of lysosomal storage disease. Hum Gene Ther. 2014;25(7):609–18.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Mingozzi F, Liu YL, Dobrzynski E, Kaufhold A, Liu JH, Wang Y, et al. Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer. J Clin Invest. 2003;111(9):1347–56.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Mingozzi F, Hasbrouck NC, Basner-Tschakarjan E, Edmonson SA, Hui DJ, Sabatino DE, et al. Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver. Blood. 2007;110(7):2334–41.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Dobrzynski E, Mingozzi F, Liu YL, Bendo E, Cao O, Wang L, et al. Induction of antigen-specific CD4+ T-cell anergy and deletion by in vivo viral gene transfer. Blood. 2004;104(4):969–77.PubMedCrossRefGoogle Scholar
  135. 135.
    Cao O, Dobrzynski E, Wang L, Nayak S, Mingle B, Terhorst C, et al. Induction and role of regulatory CD4+CD25+ T cells in tolerance to the transgene product following hepatic in vivo gene transfer. Blood. 2007;110(4):1132–40.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Mingozzi F, Maus MV, Hui DJ, Sabatino DE, Murphy SL, Rasko JE, et al. CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nat Med. 2007;13(4):419–22.PubMedCrossRefGoogle Scholar
  137. 137.
    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.PubMedCrossRefGoogle Scholar
  138. 138.
    Erles K, Sebokova P, Schlehofer JR. Update on the prevalence of serum antibodies (IgG and IgM) to adeno-associated virus (AAV). J Med Virol. 1999;59(3):406–11.PubMedCrossRefGoogle Scholar
  139. 139.
    Veron P, Leborgne C, Monteilhet V, Boutin S, Martin S, Moullier P, et al. Humoral and cellular capsid-specific immune responses to adeno-associated virus type 1 in randomized healthy donors. J Immunol. 2012;188(12):6418–24.PubMedCrossRefGoogle Scholar
  140. 140.
    Vandamme C, Adjali O, Mingozzi F. Unraveling the complex story of immune responses to AAV vectors trial after trial. Hum Gene Ther. 2017;28(11):1061–74.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Finn JD, Hui D, Downey HD, Dunn D, Pien GC, Mingozzi F, et al. Proteasome inhibitors decrease AAV2 capsid derived peptide epitope presentation on MHC class I following transduction. Mol Ther. 2010;18(1):135–42.PubMedCrossRefGoogle Scholar
  142. 142.
    Pien GC, Basner-Tschakarjan E, Hui DJ, Mentlik AN, Finn JD, Hasbrouck NC, et al. Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors. J Clin Invest. 2009;119(6):1688–95.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Jiang H, Couto LB, Patarroyo-White S, Liu T, Nagy D, Vargas JA, et al. Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy. Blood. 2006;108(10):3321–8.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    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.PubMedCrossRefGoogle Scholar
  146. 146.
    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.PubMedCrossRefGoogle Scholar
  147. 147.
    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.PubMedCrossRefGoogle Scholar
  148. 148.
    Mingozzi F, High KA. Overcoming the host immune response to adeno-associated virus gene delivery vectors: the race between clearance, tolerance, neutralization, and escape. Annu Rev Virol. 2017;4(1):511–34.PubMedCrossRefGoogle Scholar
  149. 149.
    Russell DW, Hirata RK. Human gene targeting by viral vectors. Nat Genet. 1998;18(4):325–30.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Sedivy JM, Sharp PA. Positive genetic selection for gene disruption in mammalian cells by homologous recombination. Proc Natl Acad Sci U S A. 1989;86(1):227–31.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Miller DG, Wang PR, Petek LM, Hirata RK, Sands MS, Russell DW. Gene targeting in vivo by adeno-associated virus vectors. Nat Biotechnol. 2006;24(8):1022–6.PubMedCrossRefGoogle Scholar
  152. 152.
    Rouet P, Smih F, Jasin M. Introduction of double-strand breaks into the genome of mouse cells by expression of a rare-cutting endonuclease. Mol Cell Biol. 1994;14(12):8096–106.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Rouet P, Smih F, Jasin M. Expression of a site-specific endonuclease stimulates homologous recombination in mammalian cells. Proc Natl Acad Sci U S A. 1994;91(13):6064–8.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Smih F, Rouet P, Romanienko PJ, Jasin M. Double-strand breaks at the target locus stimulate gene targeting in embryonic stem cells. Nucleic Acids Res. 1995;23(24):5012–9.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Ceccaldi R, Rondinelli B, D'Andrea AD. Repair pathway choices and consequences at the double-strand break. Trends Cell Biol. 2016;26(1):52–64.PubMedCrossRefGoogle Scholar
  156. 156.
    Shibata A, Jeggo PA. DNA double-strand break repair in a cellular context. Clin Oncol. 2014;26(5):243–9.CrossRefGoogle Scholar
  157. 157.
    Cox DB, Platt RJ, Zhang F. Therapeutic genome editing: prospects and challenges. Nat Med. 2015;21(2):121–31.PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Carroll D. Genome engineering with targetable nucleases. Annu Rev Biochem. 2014;83:409–39.PubMedCrossRefGoogle Scholar
  159. 159.
    Gaj T, Gersbach CA, Barbas CF 3rd. ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol. 2013;31(7):397–405.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Urnov FD, Rebar EJ, Holmes MC, Zhang HS, Gregory PD. Genome editing with engineered zinc finger nucleases. Nat Rev Genet. 2010;11(9):636–46.PubMedCrossRefGoogle Scholar
  161. 161.
    Li L, Wu LP, Chandrasegaran S. Functional domains in Fok I restriction endonuclease. Proc Natl Acad Sci U S A. 1992;89(10):4275–9.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Li T, Huang S, Jiang WZ, Wright D, Spalding MH, Weeks DP, et al. TAL nucleases (TALNs): hybrid proteins composed of TAL effectors and FokI DNA-cleavage domain. Nucleic Acids Res. 2011;39(1):359–72.PubMedCrossRefGoogle Scholar
  163. 163.
    Cermak T, Doyle EL, Christian M, Wang L, Zhang Y, Schmidt C, et al. Efficient design and assembly of custom TALEN and other TAL effector-based constructs for DNA targeting. Nucleic Acids Res. 2011;39(12):e82.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Deng D, Yan C, Pan X, Mahfouz M, Wang J, Zhu JK, et al. Structural basis for sequence-specific recognition of DNA by TAL effectors. Science. 2012;335(6069):720–3.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Morbitzer R, Romer P, Boch J, Lahaye T. Regulation of selected genome loci using de novo-engineered transcription activator-like effector (TALE)-type transcription factors. Proc Natl Acad Sci U S A. 2010;107(50):21617–22.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Mussolino C, Morbitzer R, Lutge F, Dannemann N, Lahaye T, Cathomen T. A novel TALE nuclease scaffold enables high genome editing activity in combination with low toxicity. Nucleic Acids Res. 2011;39(21):9283–93.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Wiedenheft B, Sternberg SH, Doudna JA. RNA-guided genetic silencing systems in bacteria and archaea. Nature. 2012;482(7385):331–8.PubMedCrossRefGoogle Scholar
  168. 168.
    Fineran PC, Charpentier E. Memory of viral infections by CRISPR-Cas adaptive immune systems: acquisition of new information. Virology. 2012;434(2):202–9.PubMedCrossRefGoogle Scholar
  169. 169.
    Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337(6096):816–21.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Kleinstiver BP, Pattanayak V, Prew MS, Tsai SQ, Nguyen NT, Zheng Z, et al. High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects. Nature. 2016;529(7587):490–5.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    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.PubMedCrossRefGoogle Scholar
  172. 172.
    Casini A, Olivieri M, Petris G, Montagna C, Reginato G, Maule G, et al. A highly specific SpCas9 variant is identified by in vivo screening in yeast. Nat Biotechnol. 2018;36:265–71.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Liang X, Potter J, Kumar S, Zou Y, Quintanilla R, Sridharan M, et al. Rapid and highly efficient mammalian cell engineering via Cas9 protein transfection. J Biotechnol. 2015;208:44–53.PubMedCrossRefGoogle Scholar
  175. 175.
    Ramakrishna S, Kwaku Dad AB, Beloor J, Gopalappa R, Lee SK, Kim H. Gene disruption by cell-penetrating peptide-mediated delivery of Cas9 protein and guide RNA. Genome Res. 2014;24(6):1020–7.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Yin H, Song CQ, Dorkin JR, Zhu LJ, Li Y, Wu Q, et al. Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo. Nat Biotechnol. 2016;34(3):328–33.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Petris G, Casini A, Montagna C, Lorenzin F, Prandi D, Romanel A, et al. Hit and go CAS9 delivered through a lentiviral based self-limiting circuit. Nat Commun. 2017;8:15334.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37(2):161–5.PubMedCrossRefGoogle Scholar
  179. 179.
    Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264–72.PubMedCrossRefGoogle Scholar
  180. 180.
    Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a southern African population. Atherosclerosis. 2007;193(2):445–8.PubMedCrossRefGoogle Scholar
  181. 181.
    Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet. 2006;79(3):514–23.PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Denis M, Marcinkiewicz J, Zaid A, Gauthier D, Poirier S, Lazure C, et al. Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation. 2012;125(7):894–901.PubMedCrossRefGoogle Scholar
  183. 183.
    Ding Q, Strong A, Patel KM, Ng SL, Gosis BS, Regan SN, et al. Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ Res. 2014;115(5):488–92.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Wang X, Raghavan A, Chen T, Qiao L, Zhang Y, Ding Q, et al. CRISPR-Cas9 targeting of PCSK9 in human hepatocytes in vivo-brief report. Arterioscler Thromb Vasc Biol. 2016;36(5):783–6.PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Pankowicz FP, Barzi M, Legras X, Hubert L, Mi T, Tomolonis JA, et al. Reprogramming metabolic pathways in vivo with CRISPR/Cas9 genome editing to treat hereditary tyrosinaemia. Nat Commun. 2016;7:12642.PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Russo P, O’Regan S. Visceral pathology of hereditary tyrosinemia type I. Am J Hum Genet. 1990;47(2):317–24.PubMedPubMedCentralGoogle Scholar
  187. 187.
    Paulk NK, Wursthorn K, Wang Z, Finegold MJ, Kay MA, Grompe M. Adeno-associated virus gene repair corrects a mouse model of hereditary tyrosinemia in vivo. Hepatology. 2010;51(4):1200–8.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Yin H, Xue W, Chen S, Bogorad RL, Benedetti E, Grompe M, et al. Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nat Biotechnol. 2014;32(6):551–3.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Barzel A, Paulk NK, Shi Y, Huang Y, Chu K, Zhang F, et al. Promoterless gene targeting without nucleases ameliorates haemophilia B in mice. Nature. 2015;517(7534):360–4.PubMedCrossRefGoogle Scholar
  190. 190.
    Borel F, Tang Q, Gernoux G, Greer C, Wang Z, Barzel A, et al. Survival advantage of both human hepatocyte xenografts and genome-edited hepatocytes for treatment of alpha-1 antitrypsin deficiency. Mol Ther. 2017;25(11):2477–89.PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Yang Y, Wang L, Bell P, McMenamin D, He Z, White J, et al. A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice. Nat Biotechnol. 2016;34(3):334–8.PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Connelly JP, Barker JC, Pruett-Miller S, Porteus MH. Gene correction by homologous recombination with zinc finger nucleases in primary cells from a mouse model of a generic recessive genetic disease. Mol Ther. 2010;18(6):1103–10.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    DeKelver RC, Choi VM, Moehle EA, Paschon DE, Hockemeyer D, Meijsing SH, et al. Functional genomics, proteomics, and regulatory DNA analysis in isogenic settings using zinc finger nuclease-driven transgenesis into a safe harbor locus in the human genome. Genome Res. 2010;20(8):1133–42.PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Hockemeyer D, Soldner F, Beard C, Gao Q, Mitalipova M, DeKelver RC, et al. Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases. Nat Biotechnol. 2009;27(9):851–7.PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Kotin RM, Linden RM, Berns KI. Characterization of a preferred site on human chromosome 19q for integration of adeno-associated virus DNA by non-homologous recombination. EMBO J. 1992;11(13):5071–8.PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Li H, Haurigot V, Doyon Y, Li T, Wong SY, Bhagwat AS, et al. In vivo genome editing restores haemostasis in a mouse model of haemophilia. Nature. 2011;475(7355):217–21.PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Anguela XM, Sharma R, Doyon Y, Miller JC, Li H, Haurigot V, et al. Robust ZFN-mediated genome editing in adult hemophilic mice. Blood. 2013;122(19):3283–7.PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Sharma R, Anguela XM, Doyon Y, Wechsler T, DeKelver RC, Sproul S, et al. In vivo genome editing of the albumin locus as a platform for protein replacement therapy. Blood. 2015;126(15):1777–84.PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Chew WL, Tabebordbar M, Cheng JK, Mali P, Wu EY, Ng AH, et al. A multifunctional AAV-CRISPR-Cas9 and its host response. Nat Methods. 2016;13(10):868–74.PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Porro F, Bortolussi G, Barzel A, De Caneva A, Iaconcig A, Vodret S, et al. Promoterless gene targeting without nucleases rescues lethality of a Crigler-Najjar syndrome mouse model. EMBO Mol Med. 2017;9(10):1346–55.PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Nygaard S, Barzel A, Haft A, Major A, Finegold M, Kay MA, et al. A universal system to select gene-modified hepatocytes in vivo. Sci Transl Med. 2016;8(342):342ra79.PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Adam R, Karam V, Delvart V, O’Grady J, Mirza D, Klempnauer J, et al. Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR). J Hepatol. 2012;57(3):675–88.PubMedCrossRefGoogle Scholar
  203. 203.
    Lindberg RL, Porcher C, Grandchamp B, Ledermann B, Burki K, Brandner S, et al. Porphobilinogen deaminase deficiency in mice causes a neuropathy resembling that of human hepatic porphyria. Nat Genet. 1996;12(2):195–9.PubMedCrossRefGoogle Scholar
  204. 204.
    Unzu C, Sampedro A, Mauleon I, Vanrell L, Dubrot J, de Salamanca RE, et al. Porphobilinogen deaminase over-expression in hepatocytes, but not in erythrocytes, prevents accumulation of toxic porphyrin precursors in a mouse model of acute intermittent porphyria. J Hepatol. 2010;52(3):417–24.PubMedCrossRefGoogle Scholar
  205. 205.
    Carlson JA, Rogers BB, Sifers RN, Finegold MJ, Clift SM, DeMayo FJ, et al. Accumulation of PiZ alpha 1-antitrypsin causes liver damage in transgenic mice. J Clin Invest. 1989;83(4):1183–90.PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Cruz PE, Mueller C, Cossette TL, Golant A, Tang Q, Beattie SG, et al. In vivo post-transcriptional gene silencing of alpha-1 antitrypsin by adeno-associated virus vectors expressing siRNA. Lab Invest. 2007;87(9):893–902.PubMedCrossRefGoogle Scholar
  207. 207.
    Chiuchiolo MJ, Crystal RG. Gene therapy for Alpha-1 antitrypsin deficiency lung disease. Ann Am Thorac Soc. 2016;13(Suppl 4):S352–69.PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Conlon TJ, Cossette T, Erger K, Choi YK, Clarke T, Scott-Jorgensen M, et al. Efficient hepatic delivery and expression from a recombinant adeno-associated virus 8 pseudotyped alpha1-antitrypsin vector. Mol Ther. 2005;12(5):867–75.PubMedCrossRefGoogle Scholar
  209. 209.
    Morral N, Parks RJ, Zhou H, Langston C, Schiedner G, Quinones J, et al. High doses of a helper-dependent adenoviral vector yield supraphysiological levels of alpha1-antitrypsin with negligible toxicity. Hum Gene Ther. 1998;9(18):2709–16.PubMedCrossRefGoogle Scholar
  210. 210.
    Schiedner G, Morral N, Parks RJ, Wu Y, Koopmans SC, Langston C, et al. Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity. Nat Genet. 1998;18(2):180–3.PubMedCrossRefGoogle Scholar
  211. 211.
    Patejunas G, Bradley A, Beaudet AL, O’Brien WE. Generation of a mouse model for citrullinemia by targeted disruption of the argininosuccinate synthetase gene. Somat Cell Mol Genet. 1994;20(1):55–60.PubMedCrossRefGoogle Scholar
  212. 212.
    Perez CJ, Jaubert J, Guenet JL, Barnhart KF, Ross-Inta CM, Quintanilla VC, et al. Two hypomorphic alleles of mouse Ass1 as a new animal model of citrullinemia type I and other hyperammonemic syndromes. Am J Pathol. 2010;177(4):1958–68.PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Chandler RJ, Tarasenko TN, Cusmano-Ozog K, Sun Q, Sutton VR, Venditti CP, et al. Liver-directed adeno-associated virus serotype 8 gene transfer rescues a lethal murine model of citrullinemia type 1. Gene Ther. 2013;20(12):1188–91.PubMedPubMedCentralCrossRefGoogle Scholar
  214. 214.
    Kok CY, Cunningham SC, Carpenter KH, Dane AP, Siew SM, Logan GJ, et al. Adeno-associated virus-mediated rescue of neonatal lethality in argininosuccinate synthetase-deficient mice. Mol Ther. 2013;21(10):1823–31.PubMedPubMedCentralCrossRefGoogle Scholar
  215. 215.
    Ye X, Whiteman B, Jerebtsova M, Batshaw ML. Correction of argininosuccinate synthetase (AS) deficiency in a murine model of citrullinemia with recombinant adenovirus carrying human AS cDNA. Gene Ther. 2000;7(20):1777–82.PubMedCrossRefGoogle Scholar
  216. 216.
    Gunn CH. Hereditary acholuric jaundice in a new mutant strain of rats. J Hered. 1934;29:137–9.CrossRefGoogle Scholar
  217. 217.
    Toietta G, Mane VP, Norona WS, Finegold MJ, Ng P, McDonagh AF, et al. Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector. Proc Natl Acad Sci U S A. 2005;102(11):3930–5.PubMedPubMedCentralCrossRefGoogle Scholar
  218. 218.
    Seppen J, van der Rijt R, Looije N, van Til NP, Lamers WH, Oude Elferink RP. Long-term correction of bilirubin UDPglucuronyltransferase deficiency in rats by in utero lentiviral gene transfer. Mol Ther. 2003;8(4):593–9.PubMedCrossRefGoogle Scholar
  219. 219.
    Seppen J, van Til NP, van der Rijt R, Hiralall JK, Kunne C, Elferink RP. Immune response to lentiviral bilirubin UDP-glucuronosyltransferase gene transfer in fetal and neonatal rats. Gene Ther. 2006;13(8):672–7.PubMedCrossRefGoogle Scholar
  220. 220.
    Pastore N, Nusco E, Piccolo P, Castaldo S, Vanikova J, Vetrini F, et al. Improved efficacy and reduced toxicity by ultrasound-guided intrahepatic injections of helper-dependent adenoviral vector in Gunn rats. Hum Gene Ther Methods. 2013;24(5):321–7.PubMedCrossRefGoogle Scholar
  221. 221.
    Flageul M, Aubert D, Pichard V, Nguyen TH, Nowrouzi A, Schmidt M, et al. Transient expression of genes delivered to newborn rat liver using recombinant adeno-associated virus 2/8 vectors. J Gene Med. 2009;11(8):689–96.PubMedCrossRefGoogle Scholar
  222. 222.
    Montenegro-Miranda PS, Paneda A, ten Bloemendaal L, Duijst S, de Waart DR, Aseguinolaza GG, et al. Adeno-associated viral vector serotype 5 poorly transduces liver in rat models. PLoS One. 2013;8(12):e82597.PubMedPubMedCentralCrossRefGoogle Scholar
  223. 223.
    Nguyen TH, Bellodi-Privato M, Aubert D, Pichard V, Myara A, Trono D, et al. Therapeutic lentivirus-mediated neonatal in vivo gene therapy in hyperbilirubinemic Gunn rats. Mol Ther. 2005;12(5):852–9.PubMedCrossRefGoogle Scholar
  224. 224.
    Schmitt F, Remy S, Dariel A, Flageul M, Pichard V, Boni S, et al. Lentiviral vectors that express UGT1A1 in liver and contain miR-142 target sequences normalize hyperbilirubinemia in Gunn rats. Gastroenterology. 2010;139(3):999–1007, 07 e1–2.CrossRefGoogle Scholar
  225. 225.
    Nguyen TH, Aubert D, Bellodi-Privato M, Flageul M, Pichard V, Jaidane-Abdelghani Z, et al. Critical assessment of lifelong phenotype correction in hyperbilirubinemic Gunn rats after retroviral mediated gene transfer. Gene Ther. 2007;14(17):1270–7.PubMedCrossRefGoogle Scholar
  226. 226.
    Wang X, Sarkar DP, Mani P, Steer CJ, Chen Y, Guha C, et al. Long-term reduction of jaundice in Gunn rats by nonviral liver-targeted delivery of sleeping beauty transposon. Hepatology. 2009;50(3):815–24.PubMedPubMedCentralCrossRefGoogle Scholar
  227. 227.
    Nguyen N, Bonzo JA, Chen S, Chouinard S, Kelner MJ, Hardiman G, et al. Disruption of the ugt1 locus in mice resembles human Crigler-Najjar type I disease. J Biol Chem. 2008;283(12):7901–11.PubMedCrossRefGoogle Scholar
  228. 228.
    Greig JA, Nordin JML, Draper C, Bell P, Wilson JM. AAV8 gene therapy rescues the newborn phenotype of a mouse model of Crigler-Najjar. Hum Gene Ther. 2018;29(7):763–70.PubMedCrossRefGoogle Scholar
  229. 229.
    Ishibashi S, Brown MS, Goldstein JL, Gerard RD, Hammer RE, Herz J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest. 1993;92(2):883–93.PubMedPubMedCentralCrossRefGoogle Scholar
  230. 230.
    Powell-Braxton L, Veniant M, Latvala RD, Hirano KI, Won WB, Ross J, et al. A mouse model of human familial hypercholesterolemia: markedly elevated low density lipoprotein cholesterol levels and severe atherosclerosis on a low-fat chow diet. Nat Med. 1998;4(8):934–8.PubMedCrossRefGoogle Scholar
  231. 231.
    Lebherz C, Gao G, Louboutin JP, Millar J, Rader D, Wilson JM. Gene therapy with novel adeno-associated virus vectors substantially diminishes atherosclerosis in a murine model of familial hypercholesterolemia. J Gene Med. 2004;6(6):663–72.PubMedCrossRefGoogle Scholar
  232. 232.
    Lebherz C, Sanmiguel J, Wilson JM, Rader DJ. Gene transfer of wild-type apoA-I and apoA-I Milano reduce atherosclerosis to a similar extent. Cardiovasc Diabetol. 2007;6:15.PubMedPubMedCentralCrossRefGoogle Scholar
  233. 233.
    Chen SJ, Sanmiguel J, Lock M, McMenamin D, Draper C, Limberis MP, et al. Biodistribution of AAV8 vectors expressing human low-density lipoprotein receptor in a mouse model of homozygous familial hypercholesterolemia.Human gene therapy. Clin Dev. 2013;24(4):154–60.Google Scholar
  234. 234.
    Chen SJ, Rader DJ, Tazelaar J, Kawashiri M, Gao G, Wilson JM. Prolonged correction of hyperlipidemia in mice with familial hypercholesterolemia using an adeno-associated viral vector expressing very-low-density lipoprotein receptor. Mol Ther. 2000;2(3):256–61.PubMedCrossRefGoogle Scholar
  235. 235.
    Kassim SH, Li H, Bell P, Somanathan S, Lagor W, Jacobs F, et al. Adeno-associated virus serotype 8 gene therapy leads to significant lowering of plasma cholesterol levels in humanized mouse models of homozygous and heterozygous familial hypercholesterolemia. Hum Gene Ther. 2013;24(1):19–26.PubMedCrossRefGoogle Scholar
  236. 236.
    Kassim SH, Li H, Vandenberghe LH, Hinderer C, Bell P, Marchadier D, et al. Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis. PLoS One. 2010;5(10):e13424.PubMedPubMedCentralCrossRefGoogle Scholar
  237. 237.
    Somanathan S, Jacobs F, Wang Q, Hanlon AL, Wilson JM, Rader DJ. AAV vectors expressing LDLR gain-of-function variants demonstrate increased efficacy in mouse models of familial hypercholesterolemia. Circ Res. 2014;115(6):591–9.PubMedPubMedCentralCrossRefGoogle Scholar
  238. 238.
    Bi L, Lawler AM, Antonarakis SE, High KA, Gearhart JD, Kazazian HH Jr. Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A. Nat Genet. 1995;10(1):119–21.PubMedCrossRefGoogle Scholar
  239. 239.
    Chavez CL, Keravala A, Chu JN, Farruggio AP, Cuellar VE, Voorberg J, et al. Long-term expression of human coagulation factor VIII in a tolerant mouse model using the phiC31 integrase system. Hum Gene Ther. 2012;23(4):390–8.PubMedCrossRefGoogle Scholar
  240. 240.
    Merlin S, Cannizzo ES, Borroni E, Bruscaggin V, Schinco P, Tulalamba W, et al. A novel platform for immune tolerance induction in hemophilia A mice. Mol Ther. 2017;25(8):1815–30.PubMedPubMedCentralCrossRefGoogle Scholar
  241. 241.
    Monahan PE, Lothrop CD, Sun J, Hirsch ML, Kafri T, Kantor B, et al. 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. 2010;18(11):1907–16.PubMedPubMedCentralCrossRefGoogle Scholar
  242. 242.
    Lozier JN, Dutra A, Pak E, Zhou N, Zheng Z, Nichols TC, et al. The Chapel Hill hemophilia A dog colony exhibits a factor VIII gene inversion. Proc Natl Acad Sci U S A. 2002;99(20):12991–6.PubMedPubMedCentralCrossRefGoogle Scholar
  243. 243.
    Evans JP, Brinkhous KM, Brayer GD, Reisner HM, High KA. Canine hemophilia B resulting from a point mutation with unusual consequences. Proc Natl Acad Sci U S A. 1989;86(24):10095–9.PubMedPubMedCentralCrossRefGoogle Scholar
  244. 244.
    Mauser AE, Whitlark J, Whitney KM, Lothrop CD Jr. A deletion mutation causes hemophilia B in Lhasa Apso dogs. Blood. 1996;88(9):3451–5.PubMedGoogle Scholar
  245. 245.
    Wang L, Zoppe M, Hackeng TM, Griffin JH, Lee KF, Verma IM. A factor IX-deficient mouse model for hemophilia B gene therapy. Proc Natl Acad Sci U S A. 1997;94(21):11563–6.PubMedPubMedCentralCrossRefGoogle Scholar
  246. 246.
    Mingozzi F, Schuttrumpf J, Arruda VR, Liu Y, Liu YL, High KA, et al. Improved hepatic gene transfer by using an adeno-associated virus serotype 5 vector. J Virol. 2002;76(20):10497–502.PubMedPubMedCentralCrossRefGoogle Scholar
  247. 247.
    Arruda VR, Schuettrumpf J, Herzog RW, Nichols TC, Robinson N, Lotfi Y, et al. Safety and efficacy of factor IX gene transfer to skeletal muscle in murine and canine hemophilia B models by adeno-associated viral vector serotype 1. Blood. 2004;103(1):85–92.PubMedCrossRefGoogle Scholar
  248. 248.
    Nichols TC, Whitford MH, Arruda VR, Stedman HH, Kay MA, High KA. Translational data from adeno-associated virus-mediated gene therapy of hemophilia B in dogs. Hum Gene Ther Clin Dev. 2015;26(1):5–14.PubMedCrossRefGoogle Scholar
  249. 249.
    Wendel U, Saudubray JM, Bodner A, Schadewaldt P. Liver transplantation in maple syrup urine disease. Eur J Pediatr. 1999;158(Suppl 2):S60–4.PubMedCrossRefGoogle Scholar
  250. 250.
    Homanics GE, Skvorak K, Ferguson C, Watkins S, Paul HS. Production and characterization of murine models of classic and intermediate maple syrup urine disease. BMC Med Genet. 2006;7:33.PubMedPubMedCentralCrossRefGoogle Scholar
  251. 251.
    Johnson MT, Yang HS, Magnuson T, Patel MS. Targeted disruption of the murine dihydrolipoamide dehydrogenase gene (Dld) results in perigastrulation lethality. Proc Natl Acad Sci U S A. 1997;94(26):14512–7.PubMedPubMedCentralCrossRefGoogle Scholar
  252. 252.
    Chandler RJ, Sloan J, Fu H, Tsai M, Stabler S, Allen R, et al. Metabolic phenotype of methylmalonic acidemia in mice and humans: the role of skeletal muscle. BMC Med Genet. 2007;8:64.PubMedPubMedCentralCrossRefGoogle Scholar
  253. 253.
    Chandler RJ, Venditti CP. Pre-clinical efficacy and dosing of an AAV8 vector expressing human methylmalonyl-CoA mutase in a murine model of methylmalonic acidemia (MMA). Mol Genet Metab. 2012;107(3):617–9.PubMedPubMedCentralCrossRefGoogle Scholar
  254. 254.
    Carrillo-Carrasco N, Chandler RJ, Chandrasekaran S, Venditti CP. Liver-directed recombinant adeno-associated viral gene delivery rescues a lethal mouse model of methylmalonic acidemia and provides long-term phenotypic correction. Hum Gene Ther. 2010;21(9):1147–54.PubMedPubMedCentralCrossRefGoogle Scholar
  255. 255.
    Chandler RJ, Venditti CP. Long-term rescue of a lethal murine model of methylmalonic acidemia using adeno-associated viral gene therapy. Mol Ther. 2010;18(1):11–6.PubMedCrossRefGoogle Scholar
  256. 256.
    Chandler RJ, Venditti CP. Adenovirus-mediated gene delivery rescues a neonatal lethal murine model of mut(0) methylmalonic acidemia. Hum Gene Ther. 2008;19(1):53–60.PubMedPubMedCentralCrossRefGoogle Scholar
  257. 257.
    Senac JS, Chandler RJ, Sysol JR, Li L, Venditti CP. Gene therapy in a murine model of methylmalonic acidemia using rAAV9-mediated gene delivery. Gene Ther. 2012;19(4):385–91.PubMedCrossRefGoogle Scholar
  258. 258.
    Wong ES, McIntyre C, Peters HL, Ranieri E, Anson DS, Fletcher JM. Correction of methylmalonic aciduria in vivo using a codon-optimized lentiviral vector. Hum Gene Ther. 2014;25(6):529–38.PubMedPubMedCentralCrossRefGoogle Scholar
  259. 259.
    Hulbert LL, Doolittle DP. Abnormal skin and hair: a sex-linked mutation in the house mouse. Genetics. 1971;68:s29.Google Scholar
  260. 260.
    Cupp MB. Sparse-fur, sf. Mouse News Lett. 1958;19:37Google Scholar
  261. 261.
    Wang L, Bell P, Morizono H, He Z, Pumbo E, Yu H, et al. AAV gene therapy corrects OTC deficiency and prevents liver fibrosis in aged OTC-knock out heterozygous mice. Mol Genet Metab. 2017;120(4):299–305.PubMedPubMedCentralCrossRefGoogle Scholar
  262. 262.
    Bell P, Wang L, Chen SJ, Yu H, Zhu Y, Nayal M, et al. Effects of self-complementarity, codon optimization, transgene, and dose on liver transduction with AAV8. Hum Gene Ther Methods. 2016;27(6):228–37.PubMedPubMedCentralCrossRefGoogle Scholar
  263. 263.
    Brunetti-Pierri N, Clarke C, Mane V, Palmer DJ, Lanpher B, Sun Q, et al. Phenotypic correction of ornithine transcarbamylase deficiency using low dose helper-dependent adenoviral vectors. J Gene Med. 2008;10(8):890–6.PubMedPubMedCentralCrossRefGoogle Scholar
  264. 264.
    Mian A, McCormack WM Jr, Mane V, Kleppe S, Ng P, Finegold M, et al. Long-term correction of ornithine transcarbamylase deficiency by WPRE-mediated overexpression using a helper-dependent adenovirus. Mol Ther. 2004;10(3):492–9.PubMedCrossRefGoogle Scholar
  265. 265.
    Paulusma CC, Groen A, Kunne C, Ho-Mok KS, Spijkerboer AL, Rudi de Waart D, et al. Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport. Hepatology. 2006;44(1):195–204.CrossRefPubMedGoogle Scholar
  266. 266.
    Wang R, Salem M, Yousef IM, Tuchweber B, Lam P, Childs SJ, et al. Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis. Proc Natl Acad Sci U S A. 2001;98(4):2011–6.PubMedPubMedCentralCrossRefGoogle Scholar
  267. 267.
    Guenzel AJ, Hofherr SE, Hillestad M, Barry M, Weaver E, Venezia S, et al. Generation of a hypomorphic model of propionic acidemia amenable to gene therapy testing. Mol Ther. 2013;21(7):1316–23.PubMedPubMedCentralCrossRefGoogle Scholar
  268. 268.
    Miyazaki T, Ohura T, Kobayashi M, Shigematsu Y, Yamaguchi S, Suzuki Y, et al. Fatal propionic acidemia in mice lacking propionyl-CoA carboxylase and its rescue by postnatal, liver-specific supplementation via a transgene. J Biol Chem. 2001;276(38):35995–9.PubMedCrossRefGoogle Scholar
  269. 269.
    Hofherr SE, Senac JS, Chen CY, Palmer DJ, Ng P, Barry MA. Short-term rescue of neonatal lethality in a mouse model of propionic acidemia by gene therapy. Hum Gene Ther. 2009;20(2):169–80.PubMedPubMedCentralCrossRefGoogle Scholar
  270. 270.
    Chandler RJ, Chandrasekaran S, Carrillo-Carrasco N, Senac JS, Hofherr SE, Barry MA, et al. Adeno-associated virus serotype 8 gene transfer rescues a neonatal lethal murine model of propionic acidemia. Hum Gene Ther. 2011;22(4):477–81.PubMedCrossRefGoogle Scholar
  271. 271.
    Culiat CT, Klebig ML, Liu Z, Monroe H, Stanford B, Desai J, et al. Identification of mutations from phenotype-driven ENU mutagenesis in mouse chromosome 7. Mamm Genome. 2005;16(8):555–66.PubMedCrossRefGoogle Scholar
  272. 272.
    Aponte JL, Sega GA, Hauser LJ, Dhar MS, Withrow CM, Carpenter DA, et al. Point mutations in the murine fumarylacetoacetate hydrolase gene: animal models for the human genetic disorder hereditary tyrosinemia type 1. Proc Natl Acad Sci U S A. 2001;98(2):641–5.PubMedPubMedCentralCrossRefGoogle Scholar
  273. 273.
    Grompe M. Fah knockout animals as models for therapeutic liver repopulation. Adv Exp Med Biol. 2017;959:215–30.PubMedCrossRefGoogle Scholar
  274. 274.
    Hickey RD, Lillegard JB, Fisher JE, McKenzie TJ, Hofherr SE, Finegold MJ, et al. Efficient production of Fah-null heterozygote pigs by chimeric adeno-associated virus-mediated gene knockout and somatic cell nuclear transfer. Hepatology. 2011;54(4):1351–9.PubMedPubMedCentralCrossRefGoogle Scholar
  275. 275.
    Held PK, Olivares EC, Aguilar CP, Finegold M, Calos MP, Grompe M. In vivo correction of murine hereditary tyrosinemia type I by phiC31 integrase-mediated gene delivery. Mol Ther. 2005;11(3):399–408.PubMedCrossRefGoogle Scholar
  276. 276.
    Overturf K, Al-Dhalimy M, Ou CN, Finegold M, Tanguay R, Lieber A, et al. Adenovirus-mediated gene therapy in a mouse model of hereditary tyrosinemia type I. Hum Gene Ther. 1997;8(5):513–21.PubMedCrossRefGoogle Scholar
  277. 277.
    Montini E, Held PK, Noll M, Morcinek N, Al-Dhalimy M, Finegold M, et al. In vivo correction of murine tyrosinemia type I by DNA-mediated transposition. Mol Ther. 2002;6(6):759–69.PubMedCrossRefGoogle Scholar
  278. 278.
    Paulk NK, Pekrun K, Zhu E, Nygaard S, Li B, Xu J, et al. Bioengineered AAV capsids with combined high human liver transduction in vivo and unique humoral Seroreactivity. Mol Ther. 2018;26(1):289–303.PubMedCrossRefGoogle Scholar
  279. 279.
    Hickey RD, Mao SA, Glorioso J, Elgilani F, Amiot B, Chen H, et al. Curative ex vivo liver-directed gene therapy in a pig model of hereditary tyrosinemia type 1. Sci Transl Med. 2016;8(349):349ra99.PubMedPubMedCentralCrossRefGoogle Scholar
  280. 280.
    Schilsky ML, Stockert RJ, Sternlieb I. Pleiotropic effect of LEC mutation: a rodent model of Wilson’s disease. Am J Phys. 1994;266(5 Pt 1):G907–13.Google Scholar
  281. 281.
    Wu J, Forbes JR, Chen HS, Cox DW. The LEC rat has a deletion in the copper transporting ATPase gene homologous to the Wilson disease gene. Nat Genet. 1994;7(4):541–5.PubMedCrossRefGoogle Scholar
  282. 282.
    Buiakova OI, Xu J, Lutsenko S, Zeitlin S, Das K, Das S, et al. Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation. Hum Mol Genet. 1999;8(9):1665–71.PubMedCrossRefGoogle Scholar
  283. 283.
    Theophilos MB, Cox DW, Mercer JF. The toxic milk mouse is a murine model of Wilson disease. Hum Mol Genet. 1996;5(10):1619–24.PubMedCrossRefGoogle Scholar
  284. 284.
    Merle U, Encke J, Tuma S, Volkmann M, Naldini L, Stremmel W. Lentiviral gene transfer ameliorates disease progression in Long-Evans cinnamon rats: an animal model for Wilson disease. Scand J Gastroenterol. 2006;41(8):974–82.PubMedCrossRefGoogle Scholar
  285. 285.
    Murillo O, Luqui DM, Gazquez C, Martinez-Espartosa D, Navarro-Blasco I, Monreal JI, et al. Long-term metabolic correction of Wilson’s disease in a murine model by gene therapy. J Hepatol. 2016;64(2):419–26.PubMedCrossRefGoogle Scholar
  286. 286.
    Du H, Duanmu M, Witte D, Grabowski GA. Targeted disruption of the mouse lysosomal acid lipase gene: long-term survival with massive cholesteryl ester and triglyceride storage. Hum Mol Genet. 1998;7(9):1347–54.PubMedCrossRefGoogle Scholar
  287. 287.
    Du H, Heur M, Witte DP, Ameis D, Grabowski GA. Lysosomal acid lipase deficiency: correction of lipid storage by adenovirus-mediated gene transfer in mice. Hum Gene Ther. 2002;13(11):1361–72.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Mouse Molecular Genetics LaboratoryInternational Center for Genetic Engineering and Biotechnology (ICGEB), PadricianoTriesteItaly
  2. 2.Paediatric HepatologyGastroenterology and Transplantation, Hospital Papa Giovanni XXIIIBergamoItaly
  3. 3.INSERMÉvryFrance
  4. 4.GenethonÉvryFrance

Personalised recommendations