REFERENCES
1. Van Galen KPM, d'Oiron R, James P, et al. A new hemophilia carrier nomenclature to define hemophilia in women and girls: Communication from the SSC of the ISTH. J Thromb Haemost. 2021;19:1883-7.
2. Brinkhous KM, Sandberg H, Garris JB, et al. Purified human factor VIII procoagulant protein: comparative hemostatic response after infusions into hemophilic and von Willebrand disease dogs. Proc Natl Acad Sci USA. 1985;82:8752-6.
3. Giles AR, Tinlin S, Hoogendoorn H, et al. In vivo characterization of recombinant factor VIII in a canine model of hemophilia A (factor VIII deficiency). Blood. 1988;72:335-9.
4. Kingdon HS, Hassell TM. Hemophilic dog model for evaluating therapeutic effectiveness of plasma protein fractions. Blood. 1981;58:868-72.
5. 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.
6. Graham JB, Buckwalter JA. Canine hemophilia; observations on the course, the clotting anomaly, and the effect of blood transfusions. J Exp Med. 1949;90:97-111.
7. Switonski M. Impact of gene therapy for canine monogenic diseases on the progress of preclinical studies. J Appl Genet. 2020;61:179-86.
8. Pipe SW, Leebeek FWG, Recht M, et al. Gene therapy with etranacogene dezaparvovec for Hemophilia B. N Engl J Med. 2023;388:706-18.
9. Callan MB, Haskins ME, Wang P, Zhou S, High KA, Arruda VR. Successful phenotype improvement following gene therapy for severe hemophilia A in privately owned dogs. PLoS ONE. 2016;11:e0151800.
10. Doshi BS, Samelson-Jones BJ, Nichols TC, et al. AAV gene therapy in companion dogs with severe hemophilia: Real-world long-term data on immunogenicity, efficacy, and quality of life. Mol Ther Methods Clin Dev. 2024;32:101205.
11. Blanchette VS, Key NS, Ljung LR, et al. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost. 2014;12:1935-9.
12. Iorio A, Stonebraker JS, Chambost H, et al. Establishing the prevalence and prevalence at birth of hemophilia in males: a meta-analytic approach using national registries. Ann Intern Med. 2019;171:540-6.
13. Aslanian ME, Sharp CR, Rozanski EA, de Laforcade AM, Rishniw M, Brooks MB. Clinical outcome after diagnosis of hemophilia A in dogs. J Am Vet Med Assoc. 2014;245:677-83.
14. Brooks MB, Gu W, Barnas JL, Ray J, Ray K. A line 1 insertion in the Factor IX gene segregates with mild hemophilia B in dogs. Mamm Genome. 2003;14:788-95.
15. Brockmann M, Mensing N, von Luckner J, Müller E, Kehl A. Hemophilia A in a litter of Border Collies caused by a one base pair deletion in the F8 gene. Vet Clin Pathol. 2023;52:607-12.
16. Christopherson PW, Bacek LM, King KB, Boudreaux MK. Two novel missense mutations associated with hemophilia A in a family of Boxers, and a German Shepherd dog. Vet Clin Pathol. 2014;43:312-6.
17. Johnsen JM, Fletcher SN, Dove A, et al. Results of genetic analysis of 11 341 participants enrolled in the my life, our future hemophilia genotyping initiative in the United States. J Thromb Haemost. 2022;20:2022-34.
18. Hough C, Kamisue S, Cameron C, et al. Aberrant splicing and premature termination of transcription of the FVIII gene as a cause of severe canine hemophilia a: similarities with the intron 22 inversion mutation in human hemophilia. Thromb Haemostasis. 2017;87:659-65.
19. Lozier JN, Dutra A, Pak E, et al. The chapel hill hemophilia A dog colony exhibits a factor VIII gene inversion. Proc Natl Acad Sci USA. 2002;99:12991-6.
20. Hytönen MK, Viitanen S, Hundi S, Donner J, Lohi H, Kaukonen M. A frameshift deletion in F8 associated with hemophilia A in Labrador Retriever dogs. Anim Genet. 2023;54:606-12.
21. Mischke R, Wilhelm Ch, Czwalinna A, Varvenne M, Narten K, von Depka M. Canine haemophilia A caused by a mutation leading to a stop codon. Vet Rec. 2011;169:496b.
22. Lozier JN, Kloos MT, Merricks EP, et al. Severe hemophilia A in a male old english sheep dog with a C→T Transition that created a premature stop codon in factor VIII. Comp Med. 2016;66:405-11.
23. Kehl A, Haaland AH, Langbein-Detsch I, Mueller E. A SINE insertion in F8 gene leads to severe form of hemophilia A in a family of rhodesian ridgebacks. Genes. 2021;12:134.
24. 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 USA. 1989;86:10095-9.
25. Mauser A, Whitlark J, Whitney K, Lothrop CJ. A deletion mutation causes hemophilia B in Lhasa Apso dogs. Blood. 1996;88:3451-5.
26. Brooks MB, Gu W, Ray K. Complete deletion of factor IX gene and inhibition of factor IX activity in a Labrador Retriever with hemophilia B. J Am Vet Med Assoc. 1997;211:1418-21.
27. Gu W, Brooks M, Catalfamo J, Ray J, Ray K. Two distinct mutations cause severe hemophilia B in two unrelated canine pedigrees. Thromb Haemostasis. 2017;82:1270-5.
28. Mischke R, Kühnlein P, Kehl A, et al. G244E in the canine factor IX gene leads to severe haemophilia B in Rhodesian Ridgebacks. Vet J. 2011;187:113-8.
29. Brenig B, Steingräber L, Shan S, et al. Christmas disease in a Hovawart family resembling human hemophilia B Leyden is caused by a single nucleotide deletion in a highly conserved transcription factor binding site of the F9 gene promoter. Haematologica. 2019;104:2307-13.
30. Kuder H, Sandzhieva-Vuzzo L, Kehl A, Rappaport JM, Müller E, Giger U. A single base insertion in F9 causing hemophilia B in a family of newfoundland-parti standard poodle hybrid dogs. Genes. 2021;12:1491.
31. Srivastava A, Santagostino E, Dougall A, et al. WFH guidelines for the management of hemophilia, 3rd edition. Haemophilia. 2020;26 Suppl 6:1-158.
32. Brinkhous K, Sigman J, Read M, et al. Recombinant human factor IX: replacement therapy, prophylaxis, and pharmacokinetics in canine hemophilia B. Blood. 1996;88:2603-10.
33. Littlewood JD, Barrowcliffe TW. The development and characterisation of antibodies to human factor VIII in haemophilic dogs. Thromb Haemostasis. 2018;57:314-21.
34. Sabatino DE, Freguia CF, Toso R, et al. Recombinant canine B-domain-deleted FVIII exhibits high specific activity and is safe in the canine hemophilia A model. Blood. 2009;114:4562-5.
35. Stokol T, Parry B. Efficacy of fresh-frozen plasma and cryoprecipitate in dogs with von Willebrand's disease or hemophilia A. J Vet Intern Med. 1998;12:84-92.
36. Pipe SW, Sabatino DE, Nugent DJ, et al. Executive summary of the NHLBI state of the science (SOS) workshop: overview and next steps in generating a national blueprint for future research on factor VIII inhibitors. Haemophilia. 2019;25:610-5.
37. DiMichele DM. Inhibitors in childhood hemophilia A: genetic and treatment-related risk factors for development and eradication. Pediatr Blood Cancer. 2013;60 Suppl 1:S30-3.
38. DiMichele D. Inhibitor development in haemophilia B: an orphan disease in need of attention. Br J Haematol. 2007;138:305-15.
39. Arruda VR, Samelson-Jones BJ. Gene therapy for immune tolerance induction in hemophilia with inhibitors. J Thromb Haemost. 2016;14:1121-34.
40. Nichols TC, Hough C, Agersø H, Ezban M, Lillicrap D. Canine models of inherited bleeding disorders in the development of coagulation assays, novel protein replacement and gene therapies. J Thromb Haemost. 2016;14:894-905.
41. Brinkhous KM, Hedner U, Garris JB, Diness V, Read MS. Effect of recombinant factor VIIa on the hemostatic defect in dogs with hemophilia A, hemophilia B, and von Willebrand disease. Proc Natl Acad Sci USA. 1989;86:1382-6.
42. Othman M, Powell S, Hopman WM, Lillicrap D. Variability of thromboelastographic responses following the administration of rFVIIa to haemophilia A dogs supports the individualization of therapy with a global test of haemostasis. Haemophilia. 2010;16:919-25.
43. Knudsen T, Kristensen AT, Nichols TC, et al. Pharmacokinetics, pharmacodynamics and safety of recombinant canine FVIIa in a study dosing one haemophilia A and one haemostatically normal dog. Haemophilia. 2011;17:962-70.
44. Broze GJ, Higuchi D. Coagulation-dependent inhibition of fibrinolysis: role of carboxypeptidase-U and the premature lysis of clots from hemophilic plasma. Blood. 1996;88:3815-23.
45. Hvas AM, Sørensen HT, Norengaard L, Christiansen K, Ingerslev J, Sørensen B. Tranexamic acid combined with recombinant factor VIII increases clot resistance to accelerated fibrinolysis in severe hemophilia A. J Thromb Haemost. 2007;5:2408-14.
46. Strilchuk AW, Hur WS, Batty P, et al. Lipid nanoparticles and siRNA targeting plasminogen provide lasting inhibition of fibrinolysis in mouse and dog models of hemophilia A. Sci Transl Med. 2024;16:eadh0027.
47. Guillet B, Pawlowski M, Boisseau P, et al. Genotype-dependent response to desmopressin in hemophilia A and proposal of a predictive response score. Thromb Haemostasis. 2024;124:922-36.
48. Sato I, Parry BW. Effect of desmopressin on plasma factor VIII and von Willebrand factor concentrations in Greyhounds. Aust Vet J. 1998;76:809-12.
49. Xu L, Nichols TC, Sarkar R, McCorquodale S, Bellinger DA, Ponder KP. Absence of a desmopressin response after therapeutic expression of factor VIII in hemophilia A dogs with liver-directed neonatal gene therapy. Proc Natl Acad Sci USA. 2005;102:6080-5.
50. Mansell PD, Parry BW. Changes in factor VIII: coagulant activity and von Willebrand factor antigen concentration after subcutaneous injection of desmopressin in dogs with mild hemophilia A. J Vet Intern Med. 1991;5:191-4.
51. Kay MA, Rothenberg S, Landen CN, et al. In vivo gene therapy of hemophilia B: sustained partial correction in factor IX-deficient dogs. Science. 1993;262:117-9.
52. Kay MA, Landen CN, Rothenberg SR, et al. In vivo hepatic gene therapy: complete albeit transient correction of factor IX deficiency in hemophilia B dogs. Proc Natl Acad Sci USA. 1994;91:2353-7.
53. Fang B, Eisensmith RC, Wang H, et al. Gene therapy for hemophilia B: host immunosuppression prolongs the therapeutic effect of adenovirus-mediated factor IX expression. Hum Gene Ther. 1995;6:1039-44.
54. Connelly S, Mount J, Mauser A, et al. Complete short-term correction of canine hemophilia A by in vivo gene therapy. Blood. 1996;88:3846-53.
56. Flotte TR, Afione SA, Conrad C, et al. Stable in vivo expression of the cystic fibrosis transmembrane conductance regulator with an adeno-associated virus vector. Proc Natl Acad Sci USA. 1993;90:10613-7.
57. Kaplitt MG, Leone P, Samulski RJ, et al. Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Nat Genet. 1994;8:148-54.
58. Berns KI. The Gordon Wilson Lecture. From basic virology to human gene therapy. Trans Am Clin Climatol Assoc. 1999;110:75-85.
59. Doshi BS, Arruda VR. Gene therapy for hemophilia: what does the future hold? Ther Adv Hematol. 2018;9:273-93.
60. Wang JH, Gessler DJ, Zhan W, Gallagher TL, Gao G. Adeno-associated virus as a delivery vector for gene therapy of human diseases. Signal Transduct Target Ther. 2024;9:78.
61. Herzog RW, Hagstrom JN, Kung SH, et al. Stable gene transfer and expression of human blood coagulation factor IX after intramuscular injection of recombinant adeno-associated virus. Proc Natl Acad Sci USA. 1997;94:5804-9.
62. Monahan PE, Samulski RJ, Tazelaar J, et al. Direct intramuscular injection with recombinant AAV vectors results in sustained expression in a dog model of hemophilia. Gene Ther. 1998;5:40-9.
63. Chao H, Samulski R, Bellinger D, Monahan P, Nichols T, Walsh C. Persistent expression of canine factor IX in hemophilia B canines. Gene Ther. 1999;6:1695-704.
64. Choo KH, Gould KG, Rees DJ, Brownlee GG. Molecular cloning of the gene for human anti-haemophilic factor IX. Nature. 1982;299:178-80.
65. Gitschier J, Wood WI, Goralka TM, et al. Characterization of the human factor VIII gene. Nature. 1984;312:326-30.
66. Wood WI, Capon DJ, Simonsen CC, et al. Expression of active human factor VIII from recombinant DNA clones. Nature. 1984;312:330-7.
67. Lind P, Larsson K, Spira J, et al. Novel forms of B-domain-deleted recombinant factor VIII molecules. Construction and biochemical characterization. Eur J Biochem. 1995;232:19-27.
68. McIntosh J, Lenting PJ, Rosales C, et al. Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant. Blood. 2013;121:3335-44.
69. Pittman DD, Alderman EM, Tomkinson KN, Wang JH, Giles AR, Kaufman RJ. Biochemical, immunological, and in vivo functional characterization of B-domain-deleted factor VIII. Blood. 1993;81:2925-35.
70. Siner JI, Iacobelli NP, Sabatino DE, et al. Minimal modification in the factor VIII B-domain sequence ameliorates the murine hemophilia A phenotype. Blood. 2013;121:4396-403.
71. High KA. Theodore E. Woodward Award. AAV-mediated gene transfer for hemophilia. Trans Am Clin Climatol Assoc. 2003;114:337-51; discussion 51.
72. Crudele JM, Finn JD, Siner JI, et al. AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice. Blood. 2015;125:1553-61.
73. Nathwani AC, Rosales C, McIntosh J, 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;19:876-85.
74. George LA, Sullivan SK, Giermasz A, et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med. 2017;377:2215-27.
75. Rangarajan S, Walsh L, Lester W, et al. AAV5-factor VIII Gene transfer in severe hemophilia A. N Engl J Med. 2017;377:2519-30.
76. Pasi KJ, Rangarajan S, Mitchell N, et al. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N Engl J Med. 2020;382:29-40.
77. Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene roxaparvovec gene therapy for hemophilia A. N Engl J Med. 2022;386:1013-25.
78. Snyder RO, Miao C, Meuse L, et al. Correction of hemophilia B in canine and murine models using recombinant adeno-associated viral vectors. Nat Med. 1999;5:64-70.
79. Arruda VR, Fields PA, Milner R, et al. Lack of germline transmission of vector sequences following systemic administration of recombinant AAV-2 vector in males. Mol Ther. 2001;4:586-92.
80. Herzog RW, Mount JD, Arruda VR, High KA, Lothrop CD Jr. Muscle-directed gene transfer and transient immune suppression result in sustained partial correction of canine hemophilia B caused by a null mutation. Mol Ther. 2001;4:192-200.
81. Herzog RW, Fields PA, Arruda VR, et al. Influence of vector dose on factor IX-specific T and B cell responses in muscle-directed gene therapy. Hum Gene Ther. 2002;13:1281-91.
82. Mount JD, Herzog RW, Tillson DM, et al. Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy. Blood. 2002;99:2670-6.
83. Scallan CD, Lillicrap D, Jiang H, et al. Sustained phenotypic correction of canine hemophilia A using an adeno-associated viral vector. Blood. 2003;102:2031-7.
84. Harding TC, Koprivnikar KE, Tu GH, et al. Intravenous administration of an AAV-2 vector for the expression of factor IX in mice and a dog model of hemophilia B. Gene Ther. 2004;11:204-13.
85. Arruda VR, Stedman HH, Nichols TC, et al. Regional intravascular delivery of AAV-2-F.IX to skeletal muscle achieves long-term correction of hemophilia B in a large animal model. Blood. 2005;105:3458-64.
86. Wang L, Calcedo R, Nichols TC, et al. Sustained correction of disease in naive and AAV2-pretreated hemophilia B dogs: AAV2/8-mediated, liver-directed gene therapy. Blood. 2005;105:3079-86.
87. Jiang H, Lillicrap D, Patarroyo-White S, et al. Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs. Blood. 2006;108:107-15.
88. Sarkar R, Mucci M, Addya S, et al. Long-term efficacy of adeno-associated virus serotypes 8 and 9 in hemophilia a dogs and mice. Hum Gene Ther. 2006;17:427-39.
89. Niemeyer GP, Herzog RW, Mount J, et al. Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy. Blood. 2009;113:797-806.
90. Finn JD, Ozelo MC, Sabatino DE, et al. Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy. Blood. 2010;116:5842-8.
91. Arruda VR, Stedman HH, Haurigot V, et al. Peripheral transvenular delivery of adeno-associated viral vectors to skeletal muscle as a novel therapy for hemophilia B. Blood. 2010;115:4678-88.
92. Sabatino DE, Lange AM, Altynova ES, et al. Efficacy and safety of long-term prophylaxis in severe hemophilia A dogs following liver gene therapy using AAV vectors. Mol Ther. 2011;19:442-9.
93. Finn JD, Nichols TC, Svoronos N, 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;120:4521-3.
94. Batty P, Mo AM, Hurlbut D, et al. Long-term follow-up of liver-directed, adeno-associated vector-mediated gene therapy in the canine model of hemophilia A. Blood. 2022;140:2672-83.
95. Suber YB, Doshi BS, French RA, Merricks E, Nichols T, Samelson-Jones B. Success of immune tolerance induction after AAV gene therapy in high-responding inhibitor hemophilia a dogs may be F8 genotype dependent. Blood. 2024;144:3579.
96. Carcao M, Königs C, Andersson NG, et al. Predictors of immune tolerance induction success in 231 children with severe hemophilia A with high-titer inhibitors - lessons learned from the PedNet prospective cohort study. J Thromb Haemost. 2025;23:3134-47.
97. Hay CR, DiMichele DM; International Immune Tolerance Study. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood. 2012;119:1335-44.
98. Oomen I, Abdi A, Camelo RM, et al. Prediction of the chance of successful immune tolerance induction in persons with severe hemophilia A and inhibitors: a clinical prediction model. Res Pract Thromb Haemost. 2024;8:102580.
99. Zuccherato LW, Souza RP, Camelo RM, et al. Large deletions and small insertions and deletions in the factor VIII gene predict unfavorable immune tolerance induction outcome in people with severe hemophilia A and high-responding inhibitors. Thromb Res. 2024;242:109115.
100. Chitlur M, Warrier I, Rajpurkar M, Lusher JM. Inhibitors in factor IX deficiency a report of the ISTH-SSC international FIX inhibitor registry (1997-2006). Haemophilia. 2009;15:1027-31.
101. Scallan CD, Jiang H, Liu T, et al. Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice. Blood. 2006;107:1810-7.
102. Manno CS, Pierce GF, Arruda VR, et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med. 2006;12:342-7.
103. Boutin S, Monteilhet V, Veron P, et al. Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors. Hum Gene Ther. 2010;21:704-12.
104. Nichols T, Merricks E, Rakhe S, Samelson-Jones BJ, Pittman DD. OC69.3 Safe multi-year bleeding reduction by AAV gene therapy in neonatal and juvenile hemophilia B dogs. Available from: https://academy.isth.org/isth/2025/isth-2025-congress/4173051/tim.nichols.oc.69.3.-.safe.multi-year.bleeding.reduction.by.aav.gene.therapy.html [Last accessed on 25 Feb 2026].
105. Nguyen GN, Everett JK, Kafle S, et al. A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells. Nat Biotechnol. 2021;39:47-55.
106. Keeler AM, Zhan W, Ram S, Fitzgerald KA, Gao G. The curious case of AAV immunology. Mol Ther. 2025;33:1946-65.
107. Li H, Lin SW, Giles-Davis W, et al. A preclinical animal model to assess the effect of pre-existing immunity on AAV-mediated gene transfer. Mol Ther. 2009;17:1215-24.
108. Buchlis G, Odorizzi P, Soto PC, et al. Enhanced T cell function in a mouse model of human glycosylation. J Immunol. 2013;191:228-37.
109. Schuettrumpf J, Liu JH, Couto LB, et al. Inadvertent germline transmission of AAV2 vector: findings in a rabbit model correlate with those in a human clinical trial. Mol Ther. 2006;13:1064-73.
110. Krause F, Schmidtke K, de Vasconcelos MF, et al. A shedding analysis after AAV8 CNS injection revealed fragmented viral DNA without evidence of functional AAV particles in mice. Gene Ther. 2024;31:345-51.
111. Highlights of prescribing information; 2023. Available from: https://www.novartis.com/us-en/sites/novartis_us/files/zolgensma.pdf [Last accessed on 25 Feb 2026].
112. Fewell JG, MacLaughlin F, Mehta V, et al. Gene therapy for the treatment of hemophilia B using PINC-formulated plasmid delivered to muscle with electroporation. Mol Ther. 2001;3:574-83.
113. Wang L, Nichols TC, Read MS, Bellinger DA, Verma IM. Sustained expression of therapeutic level of factor IX in hemophilia B dogs by AAV-mediated gene therapy in liver. Mol Ther. 2000;1:154-8.
114. Keeler GD, Markusic DM, Hoffman BE. Liver induced transgene tolerance with AAV vectors. Cell Immunol. 2019;342:103728.
115. Kumar SRP, Hoffman BE, Terhorst C, de Jong YP, Herzog RW. 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. 2017;25:880-91.
116. Mingozzi F, Hasbrouck NC, Basner-Tschakarjan E, et al. Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver. Blood. 2007;110:2334-41.
117. Samelson-Jones BJ, Arruda VR. Translational potential of immune tolerance induction by AAV liver-directed factor VIII gene therapy for hemophilia A. Front Immunol. 2020;11:618.
118. Valentino LA, Ozelo MC, Herzog RW, et al. A review of the rationale for gene therapy for hemophilia A with inhibitors: one-shot tolerance and treatment? J Thromb Haemost. 2023;21:3033-44.
119. Kaczmarek R, Samelson-Jones BJ, Herzog RW. Immune tolerance induction by hepatic gene transfer: first-in-human evidence. Mol Ther. 2024;32:863-4.
120. Young G. Induction of factor VIII tolerance by hemophilia gene transfer to eradicate factor VIII inhibitors. Blood Adv. 2025;9:265-9.
121. Samelson-Jones BJ, Doshi BS, George LA. Coagulation factor VIII: biological basis of emerging hemophilia A therapies. Blood. 2024;144:2185-97.
122. Simioni P, Tormene D, Tognin G, et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med. 2009;361:1671-5.
123. Von Drygalski A, Giermasz A, Castaman G, et al. Etranacogene dezaparvovec (AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B. Blood Adv. 2019;3:3241-7.
124. Xue F, Li H, Wu X, et al. Safety and activity of an engineered, liver-tropic adeno-associated virus vector expressing a hyperactive Padua factor IX administered with prophylactic glucocorticoids in patients with haemophilia B: a single-centre, single-arm, phase 1, pilot trial. Lancet Haematol. 2022;9:e504-13.
125. Cheung AK, Hoggan MD, Hauswirth WW, Berns KI. Integration of the adeno-associated virus genome into cellular DNA in latently infected human Detroit 6 cells. J Virol. 1980;33:739-48.
126. Mccarty DM, Young SM, Samulski RJ. Integration of adeno-associated virus (AAV) and recombinant AAV vectors. Annu Rev Genet. 2004;38:819-45.
127. Morfopoulou S, Buddle S, Torres Montaguth OE, et al. Genomic investigations of unexplained acute hepatitis in children. Nature. 2023;617:564-73.
128. Servellita V, Sotomayor Gonzalez A, Lamson DM, et al. Adeno-associated virus type 2 in US children with acute severe hepatitis. Nature. 2023;617:574-80.
129. Martins KM, Breton C, Zheng Q, et al. Prevalent and disseminated recombinant and wild-type adeno-associated virus integration in macaques and humans. Hum Gene Ther. 2023;34:1081-94.
130. Bayard Q, Meunier L, Peneau C, et al. Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress. Nat Commun. 2018;9:5235.
131. Fujimoto A, Furuta M, Totoki Y, et al. Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat Genet. 2016;48:500-9.
132. Nault J, Datta S, Imbeaud S, et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet. 2015;47:1187-93.
133. Kaeppel C, Beattie SG, Fronza R, et al. A largely random AAV integration profile after LPLD gene therapy. Nat Med. 2013;19:889-91.
134. Sabatino DE, Bushman FD, Chandler RJ, et al. Evaluating the state of the science for adeno-associated virus integration: an integrated perspective. Mol Ther. 2022;30:2646-63.
135. Konkle BA, Walsh CE, Escobar MA, et al. BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression. Blood. 2021;137:763-74.
136. Reiss UM, Davidoff AM, Tuddenham EG, et al. Sustained clinical benefit of AAV gene therapy in severe hemophilia B. N Engl J Med. 2025;392:2226-34.
137. Schmidt M, Foster GR, Coppens M, et al. Molecular evaluation and vector integration analysis of HCC complicating AAV gene therapy for hemophilia B. Blood Adv. 2023;7:4966-9.
138. Van Gorder L, Doshi BS, Willis E, et al. Analysis of vector genome integrations in multicentric lymphoma after AAV gene therapy in a severe hemophilia A dog. Mol Ther Methods Clin Dev. 2023;31:101159.
139. Batty P, Fong S, Franco M, et al. Vector integration and fate in the hemophilia dog liver multiple years after AAV-FVIII gene transfer. Blood. 2024;143:2373-85.
140. Chai Z, Zhang X, Dobbins AL, et al. Dexamethasone transiently enhances transgene expression in the liver when administered at late-phase post long-term adeno-associated virus transduction. Hum Gene Ther. 2022;33:119-30.
141. Jin X, Wu X, Song J, et al. Comparative evaluation of liver-directed knockin strategies with viral and nonviral vectors in mouse inherited disease models. Mol Ther. 2025;10:S1525-0016(25)01035-4.
142. Sarangi P, Kumar N, Sambasivan R, et al. AAV mediated genome engineering with a bypass coagulation factor alleviates the bleeding phenotype in a murine model of hemophilia B. Thromb Res. 2024;238:151-60.
143. Zhao J, Tian S, Peng Z, et al. Biomembrane-inspired lipid nanoparticles enhance CRISPR-Cas9 editing for hemophilia A. J Controlled Release. 2025;386:114141.
