Guest Editor: G. Castaman GENE THERAPY FOR HEMOPHILIA: FACTS AND QUANDARIES IN THE 21ST CENTURY GENE THERAPY FOR HEMOPHILIA
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Abstract
Therapy for hemophilia has evolved in the last 40 years from plasma-based concentrates to recombinant proteins and, more recently, to non-factor therapeutics. Along this same timeline, research in adeno-associated virus (AAV) based gene therapy vectors has provided the framework for successful early phase clinical trials initially for hemophilia B (HB) and now for hemophilia A. Successive lessons learned from these early pivotal HB trials have paved the way for current advanced phase trials. Nevertheless, questions linger regarding 1) the optimal balance of vector dose to transgene expression, 2) amount and durability of transgene expression required, and 3) long-term safety. Some trials have demonstrated unique findings not seen previously regarding transient elevation of liver enzymes, immunogenicity of the vector capsid, and loss of transgene expression. This review will provide an update on the clinical AAV gene therapy trials in hemophilia and address the questions above. A thoughtful and rationally approached expansion of gene therapy to the clinics would certainly be a welcome addition to the arsenal of options for hemophilia therapy. Further, the global impact of gene therapy could be vastly improved by expanding eligibility to different patient populations and to developing nations. With the advances made to date, it is possible to envision a shift from the early modest goal of simply increasing life expectancy to a significant improvement in quality of life by reduction in spontaneous bleeding episodes and disease complications.
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References
1. Manco-Johnson, M.J., Abshire, T.C., Shapiro, A.D., Riske, B., Hacker, M.R., Kilcoyne, R., Ingram, J.D., Manco-Johnson, M.L., Funk, S., Jacobson, L., Valentino, L.A., Hoots, W.K., Buchanan, G.R., Dimichele, D., Recht, M., Brown, D., Leissinger, C., Bleak, S., Cohen, A., Mathew, P., Matsunaga, A., Medeiros, D., Nugent, D., Thomas, G.A., Thompson, A.A., Mcredmond, K., Soucie, J.M., Austin, H., and Evatt, B.L., Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med, 2007. 357(6): p. 535-544.
2. Arruda, V., Doshi, B., and Samelson-Jones, B., Novel approaches to hemophilia therapy: successes and challenges. Blood, 2017. 130(21): p. 2251-2256.
3. Arruda, V.R., Doshi, B.S., and Samelson-Jones, B.J., Emerging therapies for hemophilia: controversies and unanswered questions. F1000Res, 2018. 7.
4. Pipe, S.W., Montgomery, R.R., Pratt, K.P., Lenting, P.J., and Lillicrap, D., Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A. Blood, 2016. 128(16): p. 2007-2016.
5. Mahlangu, J., Oldenburg, J., Paz-Priel, I., Negrier, C., Niggli, M., Mancuso, M.E., Schmitt, C., Jiménez-Yuste, V., Kempton, C., Dhalluin, C., Callaghan, M.U., Bujan, W., Shima, M., Adamkewicz, J.I., Asikanius, E., Levy, G.G., and Kruse-Jarres, R., Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. New England Journal of Medicine, 2018. 379(9): p. 811-822.
6. Oldenburg, J., Mahlangu, J.N., Kim, B., Schmitt, C., Callaghan, M.U., Young, G., Santagostino, E., Kruse-Jarres, R., Negrier, C., Kessler, C., Valente, N., Asikanius, E., Levy, G.G., Windyga, J., and Shima, M., Emicizumab prophylaxis in hemophilia A with inhibitors. New England Journal of Medicine, 2017. 377(9): p. 809-818.
7. Sehgal, A., Barros, S., Ivanciu, L., Cooley, B., Qin, J., Racie, T., Hettinger, J., Carioto, M., Jiang, Y., Brodsky, J., Prabhala, H., Zhang, X., Attarwala, H., Hutabarat, R., Foster, D., Milstein, S., Charisse, K., Kuchimanchi, S., Maier, M.A., Nechev, L., Kandasamy, P., Kel'in, A.V., Nair, J.K., Rajeev, K.G., Manoharan, M., Meyers, R., Sorensen, B., Simon, A.R., Dargaud, Y., Negrier, C., Camire, R.M., and Akinc, A., An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia. Nat Med, 2015. 21(5): p. 492-497.
8. Chowdary, P., Lethagen, S., Friedrich, U., Brand, B., Hay, C., Karim, F.A., Klamroth, R., Knoebl, P., Laffan, M., Mahlangu, J., Miesbach, W., Nielsen, J.D., Martin-Salces, M., Angchaisuksiri, P., and The Explorer, I., Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial. J Thromb Haemost, 2015.
9. Hamedani, N.S., Ruhl, H., Zimmermann, J.J., Heiseler, T., Oldenburg, J., Mayer, G., Potzsch, B., and Muller, J., In Vitro Evaluation of Aptamer-Based Reversible Inhibition of Anticoagulant Activated Protein C as a Novel Supportive Hemostatic Approach. Nucleic Acid Ther, 2016. 26(6): p. 355-362.
10. Polderdijk, S.G.I., Baglin, T.P., and Huntington, J.A., Targeting activated protein C to treat hemophilia. Curr Opin Hematol, 2017. 24(5): p. 446-452.
11. Makris, M., Iorio, A., and Lenting, P.J., Emicizumab and thrombosis: The story so far. J Thromb Haemost, 2019. 17(8): p. 1269-1272.
12. Novo Nordisk pauses the clinical trials investigating concizumab (anti-TFPI mAB) in haemophilia A and B with or without inhibitors. 2020, Novo Nordisk: Bagsværd, Denmark.
13. Xu, L., Mei, M., Haskins, M.E., Nichols, T.C., O'donnell, P., Cullen, K., Dillow, A., Bellinger, D., and Ponder, K.P., Immune response after neonatal transfer of a human factor IX-expressing retroviral vector in dogs, cats, and mice. Thromb Res, 2007. 120(2): p. 269-280.
14. Xu, L., Gao, C., Sands, M.S., Cai, S.R., Nichols, T.C., Bellinger, D.A., Raymer, R.A., Mccorquodale, S., and Ponder, K.P., Neonatal or hepatocyte growth factor-potentiated adult gene therapy with a retroviral vector results in therapeutic levels of canine factor IX for hemophilia B. Blood, 2003. 101(10): p. 3924-3932.
15. Hacein-Bey-Abina, S., Von Kalle, C., Schmidt, M., Le Deist, F., Wulffraat, N., Mcintyre, E., Radford, I., Villeval, J.L., Fraser, C.C., Cavazzana-Calvo, M., and Fischer, A., A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med, 2003. 348(3): p. 255-256.
16. Arruda, V.R., Stedman, H.H., Haurigot, V., Buchlis, G., Baila, S., Favaro, P., Chen, Y., Franck, H.G., Zhou, S., Wright, J.F., Couto, L.B., Jiang, H., Pierce, G.F., Bellinger, D.A., Mingozzi, F., Nichols, T.C., and High, K.A., Peripheral transvenular delivery of adeno-associated viral vectors to skeletal muscle as a novel therapy for hemophilia B. Blood, 2010. 115(23): p. 4678-4688.
17. Haurigot, V., Mingozzi, F., Buchlis, G., Hui, D.J., Chen, Y., Basner-Tschakarjan, E., Arruda, V.R., Radu, A., Franck, H.G., Wright, J.F., Zhou, S., Stedman, H.H., Bellinger, D.A., Nichols, T.C., and High, K.A., Safety of AAV factor IX peripheral transvenular gene delivery to muscle in hemophilia B dogs. Mol Ther, 2010. 18(7): p. 1318-1329.
18. Du, L.M., Nurden, P., Nurden, A.T., Nichols, T.C., Bellinger, D.A., Jensen, E.S., Haberichter, S.L., Merricks, E., Raymer, R.A., Fang, J., Koukouritaki, S.B., Jacobi, P.M., Hawkins, T.B., Cornetta, K., Shi, Q., and Wilcox, D.A., Platelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A. Nat Commun, 2013. 4: p. 2773.
19. Mezzina, M. and Merten, O.W., Adeno-associated viruses. Methods Mol Biol, 2011. 737: p. 211-234.
20. Kotin, R.M., Siniscalco, M., Samulski, R.J., Zhu, X.D., Hunter, L., Laughlin, C.A., Mclaughlin, S., Muzyczka, N., Rocchi, M., and Berns, K.I., Site-specific integration by adeno-associated virus. Proc Natl Acad Sci U S A, 1990. 87(6): p. 2211-2215.
21. Kotin, R.M., Menninger, J.C., Ward, D.C., and Berns, K.I., Mapping and direct visualization of a region-specific viral DNA integration site on chromosome 19q13-qter. Genomics, 1991. 10(3): p. 831-834.
22. Matsushita, T., Elliger, S., Elliger, C., Podsakoff, G., Villarreal, L., Kurtzman, G.J., Iwaki, Y., and Colosi, P., Adeno-associated virus vectors can be efficiently produced without helper virus. Gene Ther, 1998. 5(7): p. 938-945.
23. Kotin, R.M., Large-scale recombinant adeno-associated virus production. Hum Mol Genet, 2011. 20(R1): p. R2-6.
24. Srivastava, A., In vivo tissue-tropism of adeno-associated viral vectors. Curr Opin Virol, 2016. 21: p. 75-80.
25. Choo, K.H., Gould, K.G., Rees, D.J., and Brownlee, G.G., Molecular cloning of the gene for human anti-haemophilic factor IX. Nature, 1982. 299(5879): p. 178-180.
26. Buchlis, G., Podsakoff, G.M., Radu, A., Hawk, S.M., Flake, A.W., Mingozzi, F., and High, K.A., Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer. Blood, 2012. 119(13): p. 3038-3041.
27. Manno, C.S., Chew, A.J., Hutchison, S., Larson, P.J., Herzog, R.W., Arruda, V.R., Tai, S.J., Ragni, M.V., Thompson, A., Ozelo, M., Couto, L.B., Leonard, D.G., Johnson, F.A., Mcclelland, A., Scallan, C., Skarsgard, E., Flake, A.W., Kay, M.A., High, K.A., and Glader, B., AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood, 2003. 101(8): p. 2963-2972.
28. Manno, C.S., Pierce, G.F., Arruda, V.R., Glader, B., Ragni, M., Rasko, J.J., Ozelo, M.C., Hoots, K., Blatt, P., Konkle, B., Dake, M., Kaye, R., Razavi, M., Zajko, A., Zehnder, J., Rustagi, P.K., Nakai, H., Chew, A., Leonard, D., Wright, J.F., Lessard, R.R., Sommer, J.M., Tigges, M., Sabatino, D., Luk, A., Jiang, H., Mingozzi, F., Couto, L., Ertl, H.C., High, K.A., and Kay, M.A., Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med, 2006. 12(3): p. 342-347.
29. Ertl, H.C.J. and High, K.A., Impact of AAV Capsid-Specific T-Cell Responses on Design and Outcome of Clinical Gene Transfer Trials with Recombinant Adeno-Associated Viral Vectors: An Evolving Controversy. Hum Gene Ther, 2017. 28(4): p. 328-337.
30. Martino, A.T., Herzog, R.W., Anegon, I., and Adjali, O., Measuring immune responses to recombinant AAV gene transfer. Methods Mol Biol, 2011. 807: p. 259-272.
31. Nathwani, A.C., Reiss, U.M., Tuddenham, E.G., Rosales, C., Chowdary, P., Mcintosh, J., Della Peruta, M., Lheriteau, E., Patel, N., Raj, D., Riddell, A., Pie, J., Rangarajan, S., Bevan, D., Recht, M., Shen, Y.M., Halka, K.G., Basner-Tschakarjan, E., Mingozzi, F., High, K.A., Allay, J., Kay, M.A., Ng, C.Y., Zhou, J., Cancio, M., Morton, C.L., Gray, J.T., Srivastava, D., Nienhuis, A.W., and Davidoff, A.M., Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med, 2014. 371(21): p. 1994-2004.
32. Nathwani, A.C., Tuddenham, E.G., Rangarajan, S., Rosales, C., Mcintosh, J., Linch, D.C., Chowdary, P., Riddell, A., Pie, A.J., Harrington, C., O'beirne, J., Smith, K., Pasi, J., Glader, B., Rustagi, P., Ng, C.Y., Kay, M.A., Zhou, J., Spence, Y., Morton, C.L., Allay, J., Coleman, J., Sleep, S., Cunningham, J.M., Srivastava, D., Basner-Tschakarjan, E., Mingozzi, F., High, K.A., Gray, J.T., Reiss, U.M., Nienhuis, A.W., and Davidoff, A.M., Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med, 2011. 365(25): p. 2357-2365.
33. George, L.A., Sullivan, S.K., Giermasz, A., Rasko, J.E.J., Samelson-Jones, B.J., Ducore, J., Cuker, A., Sullivan, L.M., Majumdar, S., Teitel, J., Mcguinn, C.E., Ragni, M.V., Luk, A.Y., Hui, D., Wright, J.F., Chen, Y., Liu, Y., Wachtel, K., Winters, A., Tiefenbacher, S., Arruda, V.R., Van Der Loo, J.C.M., Zelenaia, O., Takefman, D., Carr, M.E., Couto, L.B., Anguela, X.M., and High, K.A., Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant. N Engl J Med, 2017. 377(23): p. 2215-2227.
34. Simioni, P., Tormene, D., Tognin, G., Gavasso, S., Bulato, C., Iacobelli, N.P., Finn, J.D., Spiezia, L., Radu, C., and Arruda, V.R., X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med, 2009. 361(17): p. 1671-1675.
35. Arruda, V. and Samelson-Jones, B., Factor IX Padua: From Biochemistry to Gene Therapy. Blood, 2016. 128(22): p. SCI-9.
36. Crudele, J.M., Finn, J.D., Siner, J.I., Martin, N.B., Niemeyer, G.P., Zhou, S., Mingozzi, F., Lothrop, C.D., Jr., and Arruda, V.R., AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice. Blood, 2015. 125(10): p. 1553-1561.
37. Finn, J.D., Nichols, T.C., Svoronos, N., Merricks, E.P., Bellenger, D.A., Zhou, S., Simioni, P., High, K.A., and Arruda, V.R., 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): p. 4521-4523.
38. Monahan, P.E., Sun, J., Gui, T., Hu, G., Hannah, W.B., Wichlan, D.G., Wu, Z., Grieger, J.C., Li, C., Suwanmanee, T., Stafford, D.W., Booth, C.J., Samulski, J.J., Kafri, T., Mcphee, S.W., and Samulski, R.J., 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): p. 69-81.
39. Monahan, P.E., Walsh, C.E., Powell, J.S., Konkle, B., Josephson, N.C., Escobar, M.A., Mcphee, S.J., Litchev, B., Cecerle, M., Ewenstein, B.M., Rottensteiner, H., Rose, M.D.I., Reipert, B.M., Samulski, R.J., Orloff, J., and Scheiflinger, F., Update on phase 1/2 open-label trial of BAX335, an adeno-associated virus 8 (AAV8) vector-based gene therapy for program for phemophilia B. Journal of Thrombosis and Haemostasis, 2015. 13(Supplement 2): p. 87.
40. Chapin, J., Rottensteiner, H., Scheiflinger, F., and Monahan, P., An analysis of bleeding rates and factor IX consumption in the phase I/II BAX 335 gene therapy trial in subjects with hemophilia B. Res Pract Thromb Haemost, 2017. 1(Suppl. 1): p. 144.
41. Pierce, G. and Iorio, A., Past, present and future of haemophilia gene therapy: From vectors and transgenes to known and unknown outcomes. Haemophilia, 2018. 24: p. 60-67.
42. Chowdary, P., Shapiro, S., Davidoff, A.M., Reiss, U., Alade, R., Brooks, G., Dane, A., Mcintosh, J., Short, G., and Tuddenham, E., A single intravenous infusion of FLT180a results in factor IX activity levels of more than 40% and has the potential to provide a functional cure for patients with haemophilia B. Blood, 2018. 132(Supplement 1): p. 631-631.
43. Miesbach, W., Meijer, K., Coppens, M., Kampmann, P., Klamroth, R., Schutgens, R., Tangelder, M., Castaman, G., Schwable, J., Bonig, H., Seifried, E., Cattaneo, F., Meyer, C., and Leebeek, F.W.G., Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood, 2017.
44. Pipe, S., Giermasz, A., Castaman, G., Key, N.S., Lattimore, S.U., Leebeek, F., Miesbach, W., Recht, M., Gomez, E., and Long, A., One Year Data from a Phase 2b Trial of AMT-061 (AAV5-Padua hFIX variant), an Enhanced Vector for Gene Transfer in Adults with Severe or Moderate-Severe Hemophilia B. 2019, American Society of Hematology Washington, DC.
45. Pipe, S.W., Giermasz, A., Castaman, G., Key, N., Lattimore, S.U., Leebeek, F.W., Miesbach, W., Recht, M., Long, A., Gut, R., and Von Drygalski, A., AMT-061 (AAV5-Padua hFIX variant) an enchanced vector for gene transfer in adults with severe or moderate-severe hemophilia B: follow-up up to 9 months in a phase 2b trial, in 71st Annual National Hemophilia Foundation Bleeding Disorders Conference. 2019: Anaheim, CA.
46. Boutin, S., Monteilhet, V., Veron, P., Leborgne, C., Benveniste, O., Montus, M.F., and Masurier, C., 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): p. 704-712.
47. Majowicz, A., Nijmeijer, B., Lampen, M.H., Spronck, L., De Haan, M., Petry, H., Van Deventer, S.J., Meyer, C., Tangelder, M., and Ferreira, V., Therapeutic hFIX Activity Achieved after Single AAV5-hFIX Treatment in Hemophilia B Patients and NHPs with Pre-existing Anti-AAV5 NABs. Mol Ther Methods Clin Dev, 2019. 14: p. 27-36.
48. D'avola, D., Lopez-Franco, E., Sangro, B., Paneda, A., Grossios, N., Gil-Farina, I., Benito, A., Twisk, J., Paz, M., Ruiz, J., Schmidt, M., Petry, H., Harper, P., De Salamanca, R.E., Fontanellas, A., Prieto, J., and Gonzalez-Aseguinolaza, G., Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria. J Hepatol, 2016. 65(4): p. 776-783.
49. Lind, P., Larsson, K., Spira, J., Sydow-Backman, M., Almstedt, A., Gray, E., and Sandberg, H., Novel forms of B-domain deleted recombinant factor VIII molecules. Construction and biochemical characterization. European Journal of Biochemistry, 1995. 232: p. 19-27.
50. Pasi, K.J., Rangarajan, S., Mitchell, N., Lester, W., Symington, E., Madan, B., Laffan, M., Russell, C.B., Li, M., Pierce, G.F., and Wong, W.Y., Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A. N Engl J Med, 2020. 382(1): p. 29-40.
51. Rangarajan, S., Walsh, L., Lester, W., Perry, D., Madan, B., Laffan, M., Yu, H., Vettermann, C., Pierce, G.F., Wong, W.Y., and Pasi, K.J., AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. N Engl J Med, 2017. 377(26): p. 2519-2530.
52. High, K.A., George, L.A., Eyster, M.E., Sullivan, S.K., Ragni, M.V., Croteau, S.E., Samelson-Jones, B.J., Evans, M., Joseney-Antoine, M., and Macdougall, A., A phase 1/2 trial of investigational SPK-8011 in hemophilia A demonstrates durable expression and prevention of bleeds. Blood, 2018. 132(Supplement 1): p. 487-487.
53. Mcintosh, J., Lenting, P.J., Rosales, C., Lee, D., Rabbanian, S., Raj, D., Patel, N., Tuddenham, E.G., Christophe, O.D., Mcvey, J.H., Waddington, S., Nienhuis, A.W., Gray, J.T., Fagone, P., Mingozzi, F., Zhou, S.Z., High, K.A., Cancio, M., Ng, C.Y., Zhou, J., Morton, C.L., Davidoff, A.M., and Nathwani, A.C., Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant. Blood, 2013. 121(17): p. 3335-3344.
54. Nathwani, A.C., Tuddenham, E., Chowdary, P., Mcintosh, J., Lee, D., Rosales, C., Phillips, M., Pie, J., Junfang, Z., and Meagher, M.M., GO-8: preliminary results of a phase I/II dose escalation trial of gene therapy for haemophilia a using a novel human factor VIII variant. Blood, 2018. 132(Supplement 1): p. 489-489.
55. Mah, C., Sarkar, R., Zolotukhin, I., Schleissing, M., Xiao, X., Kazazian, H.H., and Byrne, B.J., Dual vectors expressing murine factor VIII result in sustained correction of hemophilia A mice. Hum Gene Ther, 2003. 14(2): p. 143-152.
56. Sabatino, D.E., Lange, A.M., Altynova, E.S., Sarkar, R., Zhou, S., Merricks, E.P., Franck, H.G., Nichols, T.C., Arruda, V.R., and Kazazian, H.H., Jr., Efficacy and safety of long-term prophylaxis in severe hemophilia A dogs following liver gene therapy using AAV vectors. Mol Ther, 2011. 19(3): p. 442-449.
57. Miesbach, W., Meijer, K., Coppens, M., Kampmann, P., Klamroth, D., Schutgens, R., Castaman, G., Seifried, E., Schwaeble, J., Bönig, H., Sawyer, E.K., and Leebeek, F.W.G., Stable FIX Expression and Durable Reductions in Bleeding and Factor IX Consumption for up to 4 Years Following AMT-060 Gene Therapy in Adults with Severe or Moderate-Severe Hemophilia B. Blood, 2019. 134(Supplement_1): p. 2059-2059.
58. Den Uijl, I.E., Mauser Bunschoten, E.P., Roosendaal, G., Schutgens, R.E., Biesma, D.H., Grobbee, D.E., and Fischer, K., Clinical severity of haemophilia A: does the classification of the 1950s still stand? Haemophilia, 2011. 17(6): p. 849-853.
59. Koster, T., Blann, A.D., Briet, E., Vandenbroucke, J.P., and Rosendaal, F.R., Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet, 1995. 345(8943): p. 152-155.
60. Rosendaal, F.R., High levels of factor VIII and venous thrombosis. Thromb Haemost, 2000. 83(1): p. 1-2.
61. Kyrle, P.A., Minar, E., Hirschl, M., Bialonczyk, C., Stain, M., Schneider, B., Weltermann, A., Speiser, W., Lechner, K., and Eichinger, S., High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med, 2000. 343(7): p. 457-462.
62. Iorio, A., Skinner, M.W., Clearfield, E., Messner, D., Pierce, G.F., Witkop, M., Tunis, S., and Core, H.E.M.P., Core outcome set for gene therapy in haemophilia: Results of the coreHEM multistakeholder project. Haemophilia, 2018. 24(4): p. e167-e172.
63. Nogami, K. and Shima, M., Phenotypic heterogeneity of hemostasis in severe hemophilia. Semin Thromb Hemost, 2015. 41(8): p. 826-831.
64. Pavlova, A. and Oldenburg, J., Defining severity of hemophilia: more than factor levels. Semin Thromb Hemost, 2013. 39(7): p. 702-710.
65. Doshi, B.S. and Arruda, V.R., Gene therapy for hemophilia: what does the future hold? Ther Adv Hematol, 2018. 9(9): p. 273-293.
66. Nguyen, G.N., Everett, J.K., Raymond, H., Kafle, S., Merricks, E.P., Kazazian, H.H., Nichols, T.C., Bushman, F.D., and Sabatino, D.E., Long-Term AAV-Mediated Factor VIII Expression in Nine Hemophilia A Dogs: A 10 Year Follow-up Analysis on Durability, Safety and Vector Integration. 2019, American Society of Hematology Washington, DC.
67. Nakai, H., Herzog, R.W., Hagstrom, J.N., Walter, J., Kung, S.H., Yang, E.Y., Tai, S.J., Iwaki, Y., Kurtzman, G.J., Fisher, K.J., Colosi, P., Couto, L.B., and High, K.A., Adeno-associated viral vector-mediated gene transfer of human blood coagulation factor IX into mouse liver. Blood, 1998. 91(12): p. 4600-4607.
68. Kay, M.A., Rothenberg, S., Landen, C.N., Bellinger, D.A., Leland, F., Toman, C., Finegold, M., Thompson, A.R., Read, M.S., Brinkhous, K.M., and Et Al., In vivo gene therapy of hemophilia B: sustained partial correction in factor IX-deficient dogs. Science, 1993. 262(5130): p. 117-119.
69. Kazazian, H.H., Jr., An estimated frequency of endogenous insertional mutations in humans. Nat Genet, 1999. 22(2): p. 130.
70. Epstein, S., Bauer, S., Miller, A., Pilaro, A., and Noguchi, P., FDA comments on phase I clinical trials without vector biodistribution data. Nat Genet, 1999. 22(4): p. 326.
71. Arruda, V.R., Fields, P.A., Milner, R., Wainwright, L., De Miguel, M.P., Donovan, P.J., Herzog, R.W., Nichols, T.C., Biegel, J.A., Razavi, M., Dake, M., Huff, D., Flake, A.W., Couto, L., Kay, M.A., and High, K.A., Lack of germline transmission of vector sequences following systemic administration of recombinant AAV-2 vector in males. Mol Ther, 2001. 4(6): p. 586-592.
72. Wellman, J., Mingozzi, F., Ozelo, M., Arruda, V., Podsakoff, G.M., Chen, Y., Konkle, B., Blatt, P., Hoots, K., Raffini, L., Rasko, J.E., Ragni, M., and High, K., Results from long-term follow-up of severe hemophilia B subjects previously enrolled in a clinical study of AAV2-FIX gene transfer to the liver. Molecular Therapy, 2012. 20: p. S28-S29.
73. Boyce, N., Trial halted after gene shows up in semen. Nature, 2001. 414(6865): p. 677.
74. Favaro, P., Downey, H.D., Zhou, J.S., Wright, J.F., Hauck, B., Mingozzi, F., High, K.A., and Arruda, V.R., Host and vector-dependent effects on the risk of germline transmission of AAV vectors. Mol Ther, 2009. 17(6): p. 1022-1030.
75. Schuettrumpf, J., Liu, J.H., Couto, L.B., Addya, K., Leonard, D.G., Zhen, Z., Sommer, J., and Arruda, V.R., Inadvertent germline transmission of AAV2 vector: findings in a rabbit model correlate with those in a human clinical trial. Mol Ther, 2006. 13(6): p. 1064-1073.
76. Buning, H. and Schmidt, M., Adeno-associated Vector Toxicity-To Be or Not to Be? Mol Ther, 2015. 23(11): p. 1673-1675.
77. Srivastava, A. and Carter, B.J., AAV Infection: Protection from Cancer. Hum Gene Ther, 2017. 28(4): p. 323-327.
78. Donsante, A., Miller, D.G., Li, Y., Vogler, C., Brunt, E.M., Russell, D.W., and Sands, M.S., AAV vector integration sites in mouse hepatocellular carcinoma. Science, 2007. 317(5837): p. 477.
79. Donsante, A., Vogler, C., Muzyczka, N., Crawford, J.M., Barker, J., Flotte, T., Campbell-Thompson, M., Daly, T., and Sands, M.S., Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors. Gene Ther, 2001. 8(17): p. 1343-1346.
80. Gauttier, V., Pichard, V., Aubert, D., Kaeppel, C., Schmidt, M., Ferry, N., and Conchon, S., No tumour-initiating risk associated with scAAV transduction in newborn rat liver. Gene Ther, 2013. 20(7): p. 779-784.
81. Bell, P., Wang, L., Lebherz, C., Flieder, D.B., Bove, M.S., Wu, D., Gao, G.P., Wilson, J.M., and Wivel, N.A., No evidence for tumorigenesis of AAV vectors in a large-scale study in mice. Mol Ther, 2005. 12(2): p. 299-306.
82. Li, H., Malani, N., Hamilton, S.R., Schlachterman, A., Bussadori, G., Edmonson, S.E., Shah, R., Arruda, V.R., Mingozzi, F., Wright, J.F., Bushman, F.D., and High, K.A., Assessing the potential for AAV vector genotoxicity in a murine model. Blood, 2011. 117(12): p. 3311-3319.
83. Niemeyer, G.P., Herzog, R.W., Mount, J., Arruda, V.R., Tillson, D.M., Hathcock, J., Van Ginkel, F.W., High, K.A., and Lothrop, C.D., Jr., Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy. Blood, 2009. 113(4): p. 797-806.
84. Kaeppel, C., Beattie, S.G., Fronza, R., Van Logtenstein, R., Salmon, F., Schmidt, S., Wolf, S., Nowrouzi, A., Glimm, H., Von Kalle, C., Petry, H., Gaudet, D., and Schmidt, M., A largely random AAV integration profile after LPLD gene therapy. Nat Med, 2013. 19(7): p. 889-891.
85. Gil-Farina, I., Fronza, R., Kaeppel, C., Lopez-Franco, E., Ferreira, V., D'avola, D., Benito, A., Prieto, J., Petry, H., Gonzalez-Aseguinolaza, G., and Schmidt, M., Recombinant AAV Integration Is Not Associated With Hepatic Genotoxicity in Nonhuman Primates and Patients. Mol Ther, 2016. 24(6): p. 1100-1105.
86. Chandler, R.J., Lafave, M.C., Varshney, G.K., Trivedi, N.S., Carrillo-Carrasco, N., Senac, J.S., Wu, W., Hoffmann, V., Elkahloun, A.G., Burgess, S.M., and Venditti, C.P., Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J Clin Invest, 2015. 125(2): p. 870-880.
87. Nault, J.C., Datta, S., Imbeaud, S., Franconi, A., Mallet, M., Couchy, G., Letouze, E., Pilati, C., Verret, B., Blanc, J.F., Balabaud, C., Calderaro, J., Laurent, A., Letexier, M., Bioulac-Sage, P., Calvo, F., and Zucman-Rossi, J., Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet, 2015. 47(10): p. 1187-1193.
88. Logan, G.J., Dane, A.P., Hallwirth, C.V., Smyth, C.M., Wilkie, E.E., Amaya, A.K., Zhu, E., Khandekar, N., Ginn, S.L., Liao, S.H.Y., Cunningham, S.C., Sasaki, N., Cabanes-Creus, M., Tam, P.P.L., Russell, D.W., Lisowski, L., and Alexander, I.E., Identification of liver-specific enhancer-promoter activity in the 3' untranslated region of the wild-type AAV2 genome. Nat Genet, 2017. 49(8): p. 1267-1273.
89. George, L.A., Ragni, M.V., Samelson-Jones, B.J., Cuker, A., Runoski, A.R., Cole, G., Wright, F., Chen, Y., Hui, D.J., Wachtel, K., Takefman, D., Couto, L.B., Reape, K.Z., Carr, M.E., Anguela, X.M., and Katherine A. High, M., Spk-8011: Preliminary Results from a Phase 1/2 Dose Escalation Trial of an Investigational AAV-Mediated Gene Therapy for Hemophilia A. Blood, 2017. 130(Suppl1): p. 604.
90. Mount, J.D., Herzog, R.W., Tillson, D.M., Goodman, S.A., Robinson, N., Mccleland, M.L., Bellinger, D., Nichols, T.C., Arruda, V.R., Lothrop, C.D., Jr., and High, K.A., Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy. Blood, 2002. 99(8): p. 2670-2676.
91. Finn, J.D., Ozelo, M.C., Sabatino, D.E., Franck, H.W., Merricks, E.P., Crudele, J.M., Zhou, S., Kazazian, H.H., Lillicrap, D., Nichols, T.C., and Arruda, V.R., Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy. Blood, 2010. 116(26): p. 5842-5848.
92. Van Dijk, K., Van Der Bom, J.G., Bax, K.N., Van Der Zee, D.C., and Van Den Berg, M.H., Use of implantable venous access devices in children with severe hemophilia: benefits and burden. Haematologica, 2004. 89(2): p. 189-194.
93. Hay, C.R., Dimichele, D.M., and International Immune Tolerance, S., The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood, 2012. 119(6): p. 1335-1344.
94. Arruda, V.R., Doshi, B.S., and Samelson-Jones, B.J., Novel approaches to hemophilia therapy: successes and challenges. Blood, 2017. 130(21): p. 2251-2256.
95. Stanford, S., Pink, R., Creagh, D., Clark, A., Lowe, G., Curry, N., Pasi, J., Perry, D., Fong, S., Hayes, G., Chandrakumaran, K., and Rangarajan, S., Adenovirus-associated antibodies in UK cohort of hemophilia patients: A seroprevalence study of the presence of adenovirus-associated virus vector-serotypes AAV5 and AAV8 neutralizing activity and antibodies in patients with hemophilia A. Res Pract Thromb Haemost, 2019. 3(2): p. 261-267.
96. Monteilhet, V., Saheb, S., Boutin, S., Leborgne, C., Veron, P., Montus, M.F., Moullier, P., Benveniste, O., and Masurier, C., A 10 patient case report on the impact of plasmapheresis upon neutralizing factors against adeno-associated virus (AAV) types 1, 2, 6, and 8. Mol Ther, 2011. 19(11): p. 2084-2091.
97. Unzu, C., Hervas-Stubbs, S., Sampedro, A., Mauleon, I., Mancheno, U., Alfaro, C., De Salamanca, R.E., Benito, A., Beattie, S.G., Petry, H., Prieto, J., Melero, I., and Fontanellas, A., Transient and intensive pharmacological immunosuppression fails to improve AAV-based liver gene transfer in non-human primates. J Transl Med, 2012. 10: p. 122.
98. Nathwani, A.C., Reiss, U., Tuddenham, E., Chowdary, P., Mcintosh, J., Riddell, A., Pie, J., Mahlangu, J.N., Recht, M., and Shen, Y.-M., Adeno-Associated Mediated Gene Transfer for Hemophilia B: 8 Year Follow up and Impact of Removing" Empty Viral Particles" on Safety and Efficacy of Gene Transfer. 2018, Am Soc Hematology.
99. Meliani, A., Boisgerault, F., Hardet, R., Marmier, S., Collaud, F., Ronzitti, G., Leborgne, C., Costa Verdera, H., Simon Sola, M., Charles, S., Vignaud, A., Van Wittenberghe, L., Manni, G., Christophe, O., Fallarino, F., Roy, C., Michaud, A., Ilyinskii, P., Kishimoto, T.K., and Mingozzi, F., Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration. Nat Commun, 2018. 9(1): p. 4098.
100. Machin, N., Ragni, M.V., and Smith, K.J., Gene therapy in hemophilia A: a cost-effectiveness analysis. Blood Adv, 2018. 2(14): p. 1792-1798.
101. Lang, J.F., Toulmin, S.A., Brida, K.L., Eisenlohr, L.C., and Davidson, B.L., Standard screening methods underreport AAV-mediated transduction and gene editing. Nat Commun, 2019. 10(1): p. 3415.
102. Skinner, M.W., Nugent, D., Wilton, P., O'mahony, B., Dolan, G., O'hara, J., and Berntorp, E., Achieving the unimaginable: Health equity in haemophilia. Haemophilia, 2020. 26(1): p. 17-24.
103. Lisowski, L., Dane, A.P., Chu, K., Zhang, Y., Cunningham, S.C., Wilson, E.M., Nygaard, S., Grompe, M., Alexander, I.E., and Kay, M.A., Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature, 2014. 506(7488): p. 382-386.
2. Arruda, V., Doshi, B., and Samelson-Jones, B., Novel approaches to hemophilia therapy: successes and challenges. Blood, 2017. 130(21): p. 2251-2256.
3. Arruda, V.R., Doshi, B.S., and Samelson-Jones, B.J., Emerging therapies for hemophilia: controversies and unanswered questions. F1000Res, 2018. 7.
4. Pipe, S.W., Montgomery, R.R., Pratt, K.P., Lenting, P.J., and Lillicrap, D., Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A. Blood, 2016. 128(16): p. 2007-2016.
5. Mahlangu, J., Oldenburg, J., Paz-Priel, I., Negrier, C., Niggli, M., Mancuso, M.E., Schmitt, C., Jiménez-Yuste, V., Kempton, C., Dhalluin, C., Callaghan, M.U., Bujan, W., Shima, M., Adamkewicz, J.I., Asikanius, E., Levy, G.G., and Kruse-Jarres, R., Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. New England Journal of Medicine, 2018. 379(9): p. 811-822.
6. Oldenburg, J., Mahlangu, J.N., Kim, B., Schmitt, C., Callaghan, M.U., Young, G., Santagostino, E., Kruse-Jarres, R., Negrier, C., Kessler, C., Valente, N., Asikanius, E., Levy, G.G., Windyga, J., and Shima, M., Emicizumab prophylaxis in hemophilia A with inhibitors. New England Journal of Medicine, 2017. 377(9): p. 809-818.
7. Sehgal, A., Barros, S., Ivanciu, L., Cooley, B., Qin, J., Racie, T., Hettinger, J., Carioto, M., Jiang, Y., Brodsky, J., Prabhala, H., Zhang, X., Attarwala, H., Hutabarat, R., Foster, D., Milstein, S., Charisse, K., Kuchimanchi, S., Maier, M.A., Nechev, L., Kandasamy, P., Kel'in, A.V., Nair, J.K., Rajeev, K.G., Manoharan, M., Meyers, R., Sorensen, B., Simon, A.R., Dargaud, Y., Negrier, C., Camire, R.M., and Akinc, A., An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia. Nat Med, 2015. 21(5): p. 492-497.
8. Chowdary, P., Lethagen, S., Friedrich, U., Brand, B., Hay, C., Karim, F.A., Klamroth, R., Knoebl, P., Laffan, M., Mahlangu, J., Miesbach, W., Nielsen, J.D., Martin-Salces, M., Angchaisuksiri, P., and The Explorer, I., Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial. J Thromb Haemost, 2015.
9. Hamedani, N.S., Ruhl, H., Zimmermann, J.J., Heiseler, T., Oldenburg, J., Mayer, G., Potzsch, B., and Muller, J., In Vitro Evaluation of Aptamer-Based Reversible Inhibition of Anticoagulant Activated Protein C as a Novel Supportive Hemostatic Approach. Nucleic Acid Ther, 2016. 26(6): p. 355-362.
10. Polderdijk, S.G.I., Baglin, T.P., and Huntington, J.A., Targeting activated protein C to treat hemophilia. Curr Opin Hematol, 2017. 24(5): p. 446-452.
11. Makris, M., Iorio, A., and Lenting, P.J., Emicizumab and thrombosis: The story so far. J Thromb Haemost, 2019. 17(8): p. 1269-1272.
12. Novo Nordisk pauses the clinical trials investigating concizumab (anti-TFPI mAB) in haemophilia A and B with or without inhibitors. 2020, Novo Nordisk: Bagsværd, Denmark.
13. Xu, L., Mei, M., Haskins, M.E., Nichols, T.C., O'donnell, P., Cullen, K., Dillow, A., Bellinger, D., and Ponder, K.P., Immune response after neonatal transfer of a human factor IX-expressing retroviral vector in dogs, cats, and mice. Thromb Res, 2007. 120(2): p. 269-280.
14. Xu, L., Gao, C., Sands, M.S., Cai, S.R., Nichols, T.C., Bellinger, D.A., Raymer, R.A., Mccorquodale, S., and Ponder, K.P., Neonatal or hepatocyte growth factor-potentiated adult gene therapy with a retroviral vector results in therapeutic levels of canine factor IX for hemophilia B. Blood, 2003. 101(10): p. 3924-3932.
15. Hacein-Bey-Abina, S., Von Kalle, C., Schmidt, M., Le Deist, F., Wulffraat, N., Mcintyre, E., Radford, I., Villeval, J.L., Fraser, C.C., Cavazzana-Calvo, M., and Fischer, A., A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med, 2003. 348(3): p. 255-256.
16. Arruda, V.R., Stedman, H.H., Haurigot, V., Buchlis, G., Baila, S., Favaro, P., Chen, Y., Franck, H.G., Zhou, S., Wright, J.F., Couto, L.B., Jiang, H., Pierce, G.F., Bellinger, D.A., Mingozzi, F., Nichols, T.C., and High, K.A., Peripheral transvenular delivery of adeno-associated viral vectors to skeletal muscle as a novel therapy for hemophilia B. Blood, 2010. 115(23): p. 4678-4688.
17. Haurigot, V., Mingozzi, F., Buchlis, G., Hui, D.J., Chen, Y., Basner-Tschakarjan, E., Arruda, V.R., Radu, A., Franck, H.G., Wright, J.F., Zhou, S., Stedman, H.H., Bellinger, D.A., Nichols, T.C., and High, K.A., Safety of AAV factor IX peripheral transvenular gene delivery to muscle in hemophilia B dogs. Mol Ther, 2010. 18(7): p. 1318-1329.
18. Du, L.M., Nurden, P., Nurden, A.T., Nichols, T.C., Bellinger, D.A., Jensen, E.S., Haberichter, S.L., Merricks, E., Raymer, R.A., Fang, J., Koukouritaki, S.B., Jacobi, P.M., Hawkins, T.B., Cornetta, K., Shi, Q., and Wilcox, D.A., Platelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A. Nat Commun, 2013. 4: p. 2773.
19. Mezzina, M. and Merten, O.W., Adeno-associated viruses. Methods Mol Biol, 2011. 737: p. 211-234.
20. Kotin, R.M., Siniscalco, M., Samulski, R.J., Zhu, X.D., Hunter, L., Laughlin, C.A., Mclaughlin, S., Muzyczka, N., Rocchi, M., and Berns, K.I., Site-specific integration by adeno-associated virus. Proc Natl Acad Sci U S A, 1990. 87(6): p. 2211-2215.
21. Kotin, R.M., Menninger, J.C., Ward, D.C., and Berns, K.I., Mapping and direct visualization of a region-specific viral DNA integration site on chromosome 19q13-qter. Genomics, 1991. 10(3): p. 831-834.
22. Matsushita, T., Elliger, S., Elliger, C., Podsakoff, G., Villarreal, L., Kurtzman, G.J., Iwaki, Y., and Colosi, P., Adeno-associated virus vectors can be efficiently produced without helper virus. Gene Ther, 1998. 5(7): p. 938-945.
23. Kotin, R.M., Large-scale recombinant adeno-associated virus production. Hum Mol Genet, 2011. 20(R1): p. R2-6.
24. Srivastava, A., In vivo tissue-tropism of adeno-associated viral vectors. Curr Opin Virol, 2016. 21: p. 75-80.
25. Choo, K.H., Gould, K.G., Rees, D.J., and Brownlee, G.G., Molecular cloning of the gene for human anti-haemophilic factor IX. Nature, 1982. 299(5879): p. 178-180.
26. Buchlis, G., Podsakoff, G.M., Radu, A., Hawk, S.M., Flake, A.W., Mingozzi, F., and High, K.A., Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer. Blood, 2012. 119(13): p. 3038-3041.
27. Manno, C.S., Chew, A.J., Hutchison, S., Larson, P.J., Herzog, R.W., Arruda, V.R., Tai, S.J., Ragni, M.V., Thompson, A., Ozelo, M., Couto, L.B., Leonard, D.G., Johnson, F.A., Mcclelland, A., Scallan, C., Skarsgard, E., Flake, A.W., Kay, M.A., High, K.A., and Glader, B., AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood, 2003. 101(8): p. 2963-2972.
28. Manno, C.S., Pierce, G.F., Arruda, V.R., Glader, B., Ragni, M., Rasko, J.J., Ozelo, M.C., Hoots, K., Blatt, P., Konkle, B., Dake, M., Kaye, R., Razavi, M., Zajko, A., Zehnder, J., Rustagi, P.K., Nakai, H., Chew, A., Leonard, D., Wright, J.F., Lessard, R.R., Sommer, J.M., Tigges, M., Sabatino, D., Luk, A., Jiang, H., Mingozzi, F., Couto, L., Ertl, H.C., High, K.A., and Kay, M.A., Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med, 2006. 12(3): p. 342-347.
29. Ertl, H.C.J. and High, K.A., Impact of AAV Capsid-Specific T-Cell Responses on Design and Outcome of Clinical Gene Transfer Trials with Recombinant Adeno-Associated Viral Vectors: An Evolving Controversy. Hum Gene Ther, 2017. 28(4): p. 328-337.
30. Martino, A.T., Herzog, R.W., Anegon, I., and Adjali, O., Measuring immune responses to recombinant AAV gene transfer. Methods Mol Biol, 2011. 807: p. 259-272.
31. Nathwani, A.C., Reiss, U.M., Tuddenham, E.G., Rosales, C., Chowdary, P., Mcintosh, J., Della Peruta, M., Lheriteau, E., Patel, N., Raj, D., Riddell, A., Pie, J., Rangarajan, S., Bevan, D., Recht, M., Shen, Y.M., Halka, K.G., Basner-Tschakarjan, E., Mingozzi, F., High, K.A., Allay, J., Kay, M.A., Ng, C.Y., Zhou, J., Cancio, M., Morton, C.L., Gray, J.T., Srivastava, D., Nienhuis, A.W., and Davidoff, A.M., Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med, 2014. 371(21): p. 1994-2004.
32. Nathwani, A.C., Tuddenham, E.G., Rangarajan, S., Rosales, C., Mcintosh, J., Linch, D.C., Chowdary, P., Riddell, A., Pie, A.J., Harrington, C., O'beirne, J., Smith, K., Pasi, J., Glader, B., Rustagi, P., Ng, C.Y., Kay, M.A., Zhou, J., Spence, Y., Morton, C.L., Allay, J., Coleman, J., Sleep, S., Cunningham, J.M., Srivastava, D., Basner-Tschakarjan, E., Mingozzi, F., High, K.A., Gray, J.T., Reiss, U.M., Nienhuis, A.W., and Davidoff, A.M., Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med, 2011. 365(25): p. 2357-2365.
33. George, L.A., Sullivan, S.K., Giermasz, A., Rasko, J.E.J., Samelson-Jones, B.J., Ducore, J., Cuker, A., Sullivan, L.M., Majumdar, S., Teitel, J., Mcguinn, C.E., Ragni, M.V., Luk, A.Y., Hui, D., Wright, J.F., Chen, Y., Liu, Y., Wachtel, K., Winters, A., Tiefenbacher, S., Arruda, V.R., Van Der Loo, J.C.M., Zelenaia, O., Takefman, D., Carr, M.E., Couto, L.B., Anguela, X.M., and High, K.A., Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant. N Engl J Med, 2017. 377(23): p. 2215-2227.
34. Simioni, P., Tormene, D., Tognin, G., Gavasso, S., Bulato, C., Iacobelli, N.P., Finn, J.D., Spiezia, L., Radu, C., and Arruda, V.R., X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med, 2009. 361(17): p. 1671-1675.
35. Arruda, V. and Samelson-Jones, B., Factor IX Padua: From Biochemistry to Gene Therapy. Blood, 2016. 128(22): p. SCI-9.
36. Crudele, J.M., Finn, J.D., Siner, J.I., Martin, N.B., Niemeyer, G.P., Zhou, S., Mingozzi, F., Lothrop, C.D., Jr., and Arruda, V.R., AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice. Blood, 2015. 125(10): p. 1553-1561.
37. Finn, J.D., Nichols, T.C., Svoronos, N., Merricks, E.P., Bellenger, D.A., Zhou, S., Simioni, P., High, K.A., and Arruda, V.R., 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): p. 4521-4523.
38. Monahan, P.E., Sun, J., Gui, T., Hu, G., Hannah, W.B., Wichlan, D.G., Wu, Z., Grieger, J.C., Li, C., Suwanmanee, T., Stafford, D.W., Booth, C.J., Samulski, J.J., Kafri, T., Mcphee, S.W., and Samulski, R.J., 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): p. 69-81.
39. Monahan, P.E., Walsh, C.E., Powell, J.S., Konkle, B., Josephson, N.C., Escobar, M.A., Mcphee, S.J., Litchev, B., Cecerle, M., Ewenstein, B.M., Rottensteiner, H., Rose, M.D.I., Reipert, B.M., Samulski, R.J., Orloff, J., and Scheiflinger, F., Update on phase 1/2 open-label trial of BAX335, an adeno-associated virus 8 (AAV8) vector-based gene therapy for program for phemophilia B. Journal of Thrombosis and Haemostasis, 2015. 13(Supplement 2): p. 87.
40. Chapin, J., Rottensteiner, H., Scheiflinger, F., and Monahan, P., An analysis of bleeding rates and factor IX consumption in the phase I/II BAX 335 gene therapy trial in subjects with hemophilia B. Res Pract Thromb Haemost, 2017. 1(Suppl. 1): p. 144.
41. Pierce, G. and Iorio, A., Past, present and future of haemophilia gene therapy: From vectors and transgenes to known and unknown outcomes. Haemophilia, 2018. 24: p. 60-67.
42. Chowdary, P., Shapiro, S., Davidoff, A.M., Reiss, U., Alade, R., Brooks, G., Dane, A., Mcintosh, J., Short, G., and Tuddenham, E., A single intravenous infusion of FLT180a results in factor IX activity levels of more than 40% and has the potential to provide a functional cure for patients with haemophilia B. Blood, 2018. 132(Supplement 1): p. 631-631.
43. Miesbach, W., Meijer, K., Coppens, M., Kampmann, P., Klamroth, R., Schutgens, R., Tangelder, M., Castaman, G., Schwable, J., Bonig, H., Seifried, E., Cattaneo, F., Meyer, C., and Leebeek, F.W.G., Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood, 2017.
44. Pipe, S., Giermasz, A., Castaman, G., Key, N.S., Lattimore, S.U., Leebeek, F., Miesbach, W., Recht, M., Gomez, E., and Long, A., One Year Data from a Phase 2b Trial of AMT-061 (AAV5-Padua hFIX variant), an Enhanced Vector for Gene Transfer in Adults with Severe or Moderate-Severe Hemophilia B. 2019, American Society of Hematology Washington, DC.
45. Pipe, S.W., Giermasz, A., Castaman, G., Key, N., Lattimore, S.U., Leebeek, F.W., Miesbach, W., Recht, M., Long, A., Gut, R., and Von Drygalski, A., AMT-061 (AAV5-Padua hFIX variant) an enchanced vector for gene transfer in adults with severe or moderate-severe hemophilia B: follow-up up to 9 months in a phase 2b trial, in 71st Annual National Hemophilia Foundation Bleeding Disorders Conference. 2019: Anaheim, CA.
46. Boutin, S., Monteilhet, V., Veron, P., Leborgne, C., Benveniste, O., Montus, M.F., and Masurier, C., 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): p. 704-712.
47. Majowicz, A., Nijmeijer, B., Lampen, M.H., Spronck, L., De Haan, M., Petry, H., Van Deventer, S.J., Meyer, C., Tangelder, M., and Ferreira, V., Therapeutic hFIX Activity Achieved after Single AAV5-hFIX Treatment in Hemophilia B Patients and NHPs with Pre-existing Anti-AAV5 NABs. Mol Ther Methods Clin Dev, 2019. 14: p. 27-36.
48. D'avola, D., Lopez-Franco, E., Sangro, B., Paneda, A., Grossios, N., Gil-Farina, I., Benito, A., Twisk, J., Paz, M., Ruiz, J., Schmidt, M., Petry, H., Harper, P., De Salamanca, R.E., Fontanellas, A., Prieto, J., and Gonzalez-Aseguinolaza, G., Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria. J Hepatol, 2016. 65(4): p. 776-783.
49. Lind, P., Larsson, K., Spira, J., Sydow-Backman, M., Almstedt, A., Gray, E., and Sandberg, H., Novel forms of B-domain deleted recombinant factor VIII molecules. Construction and biochemical characterization. European Journal of Biochemistry, 1995. 232: p. 19-27.
50. Pasi, K.J., Rangarajan, S., Mitchell, N., Lester, W., Symington, E., Madan, B., Laffan, M., Russell, C.B., Li, M., Pierce, G.F., and Wong, W.Y., Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A. N Engl J Med, 2020. 382(1): p. 29-40.
51. Rangarajan, S., Walsh, L., Lester, W., Perry, D., Madan, B., Laffan, M., Yu, H., Vettermann, C., Pierce, G.F., Wong, W.Y., and Pasi, K.J., AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. N Engl J Med, 2017. 377(26): p. 2519-2530.
52. High, K.A., George, L.A., Eyster, M.E., Sullivan, S.K., Ragni, M.V., Croteau, S.E., Samelson-Jones, B.J., Evans, M., Joseney-Antoine, M., and Macdougall, A., A phase 1/2 trial of investigational SPK-8011 in hemophilia A demonstrates durable expression and prevention of bleeds. Blood, 2018. 132(Supplement 1): p. 487-487.
53. Mcintosh, J., Lenting, P.J., Rosales, C., Lee, D., Rabbanian, S., Raj, D., Patel, N., Tuddenham, E.G., Christophe, O.D., Mcvey, J.H., Waddington, S., Nienhuis, A.W., Gray, J.T., Fagone, P., Mingozzi, F., Zhou, S.Z., High, K.A., Cancio, M., Ng, C.Y., Zhou, J., Morton, C.L., Davidoff, A.M., and Nathwani, A.C., Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant. Blood, 2013. 121(17): p. 3335-3344.
54. Nathwani, A.C., Tuddenham, E., Chowdary, P., Mcintosh, J., Lee, D., Rosales, C., Phillips, M., Pie, J., Junfang, Z., and Meagher, M.M., GO-8: preliminary results of a phase I/II dose escalation trial of gene therapy for haemophilia a using a novel human factor VIII variant. Blood, 2018. 132(Supplement 1): p. 489-489.
55. Mah, C., Sarkar, R., Zolotukhin, I., Schleissing, M., Xiao, X., Kazazian, H.H., and Byrne, B.J., Dual vectors expressing murine factor VIII result in sustained correction of hemophilia A mice. Hum Gene Ther, 2003. 14(2): p. 143-152.
56. Sabatino, D.E., Lange, A.M., Altynova, E.S., Sarkar, R., Zhou, S., Merricks, E.P., Franck, H.G., Nichols, T.C., Arruda, V.R., and Kazazian, H.H., Jr., Efficacy and safety of long-term prophylaxis in severe hemophilia A dogs following liver gene therapy using AAV vectors. Mol Ther, 2011. 19(3): p. 442-449.
57. Miesbach, W., Meijer, K., Coppens, M., Kampmann, P., Klamroth, D., Schutgens, R., Castaman, G., Seifried, E., Schwaeble, J., Bönig, H., Sawyer, E.K., and Leebeek, F.W.G., Stable FIX Expression and Durable Reductions in Bleeding and Factor IX Consumption for up to 4 Years Following AMT-060 Gene Therapy in Adults with Severe or Moderate-Severe Hemophilia B. Blood, 2019. 134(Supplement_1): p. 2059-2059.
58. Den Uijl, I.E., Mauser Bunschoten, E.P., Roosendaal, G., Schutgens, R.E., Biesma, D.H., Grobbee, D.E., and Fischer, K., Clinical severity of haemophilia A: does the classification of the 1950s still stand? Haemophilia, 2011. 17(6): p. 849-853.
59. Koster, T., Blann, A.D., Briet, E., Vandenbroucke, J.P., and Rosendaal, F.R., Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet, 1995. 345(8943): p. 152-155.
60. Rosendaal, F.R., High levels of factor VIII and venous thrombosis. Thromb Haemost, 2000. 83(1): p. 1-2.
61. Kyrle, P.A., Minar, E., Hirschl, M., Bialonczyk, C., Stain, M., Schneider, B., Weltermann, A., Speiser, W., Lechner, K., and Eichinger, S., High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med, 2000. 343(7): p. 457-462.
62. Iorio, A., Skinner, M.W., Clearfield, E., Messner, D., Pierce, G.F., Witkop, M., Tunis, S., and Core, H.E.M.P., Core outcome set for gene therapy in haemophilia: Results of the coreHEM multistakeholder project. Haemophilia, 2018. 24(4): p. e167-e172.
63. Nogami, K. and Shima, M., Phenotypic heterogeneity of hemostasis in severe hemophilia. Semin Thromb Hemost, 2015. 41(8): p. 826-831.
64. Pavlova, A. and Oldenburg, J., Defining severity of hemophilia: more than factor levels. Semin Thromb Hemost, 2013. 39(7): p. 702-710.
65. Doshi, B.S. and Arruda, V.R., Gene therapy for hemophilia: what does the future hold? Ther Adv Hematol, 2018. 9(9): p. 273-293.
66. Nguyen, G.N., Everett, J.K., Raymond, H., Kafle, S., Merricks, E.P., Kazazian, H.H., Nichols, T.C., Bushman, F.D., and Sabatino, D.E., Long-Term AAV-Mediated Factor VIII Expression in Nine Hemophilia A Dogs: A 10 Year Follow-up Analysis on Durability, Safety and Vector Integration. 2019, American Society of Hematology Washington, DC.
67. Nakai, H., Herzog, R.W., Hagstrom, J.N., Walter, J., Kung, S.H., Yang, E.Y., Tai, S.J., Iwaki, Y., Kurtzman, G.J., Fisher, K.J., Colosi, P., Couto, L.B., and High, K.A., Adeno-associated viral vector-mediated gene transfer of human blood coagulation factor IX into mouse liver. Blood, 1998. 91(12): p. 4600-4607.
68. Kay, M.A., Rothenberg, S., Landen, C.N., Bellinger, D.A., Leland, F., Toman, C., Finegold, M., Thompson, A.R., Read, M.S., Brinkhous, K.M., and Et Al., In vivo gene therapy of hemophilia B: sustained partial correction in factor IX-deficient dogs. Science, 1993. 262(5130): p. 117-119.
69. Kazazian, H.H., Jr., An estimated frequency of endogenous insertional mutations in humans. Nat Genet, 1999. 22(2): p. 130.
70. Epstein, S., Bauer, S., Miller, A., Pilaro, A., and Noguchi, P., FDA comments on phase I clinical trials without vector biodistribution data. Nat Genet, 1999. 22(4): p. 326.
71. Arruda, V.R., Fields, P.A., Milner, R., Wainwright, L., De Miguel, M.P., Donovan, P.J., Herzog, R.W., Nichols, T.C., Biegel, J.A., Razavi, M., Dake, M., Huff, D., Flake, A.W., Couto, L., Kay, M.A., and High, K.A., Lack of germline transmission of vector sequences following systemic administration of recombinant AAV-2 vector in males. Mol Ther, 2001. 4(6): p. 586-592.
72. Wellman, J., Mingozzi, F., Ozelo, M., Arruda, V., Podsakoff, G.M., Chen, Y., Konkle, B., Blatt, P., Hoots, K., Raffini, L., Rasko, J.E., Ragni, M., and High, K., Results from long-term follow-up of severe hemophilia B subjects previously enrolled in a clinical study of AAV2-FIX gene transfer to the liver. Molecular Therapy, 2012. 20: p. S28-S29.
73. Boyce, N., Trial halted after gene shows up in semen. Nature, 2001. 414(6865): p. 677.
74. Favaro, P., Downey, H.D., Zhou, J.S., Wright, J.F., Hauck, B., Mingozzi, F., High, K.A., and Arruda, V.R., Host and vector-dependent effects on the risk of germline transmission of AAV vectors. Mol Ther, 2009. 17(6): p. 1022-1030.
75. Schuettrumpf, J., Liu, J.H., Couto, L.B., Addya, K., Leonard, D.G., Zhen, Z., Sommer, J., and Arruda, V.R., Inadvertent germline transmission of AAV2 vector: findings in a rabbit model correlate with those in a human clinical trial. Mol Ther, 2006. 13(6): p. 1064-1073.
76. Buning, H. and Schmidt, M., Adeno-associated Vector Toxicity-To Be or Not to Be? Mol Ther, 2015. 23(11): p. 1673-1675.
77. Srivastava, A. and Carter, B.J., AAV Infection: Protection from Cancer. Hum Gene Ther, 2017. 28(4): p. 323-327.
78. Donsante, A., Miller, D.G., Li, Y., Vogler, C., Brunt, E.M., Russell, D.W., and Sands, M.S., AAV vector integration sites in mouse hepatocellular carcinoma. Science, 2007. 317(5837): p. 477.
79. Donsante, A., Vogler, C., Muzyczka, N., Crawford, J.M., Barker, J., Flotte, T., Campbell-Thompson, M., Daly, T., and Sands, M.S., Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors. Gene Ther, 2001. 8(17): p. 1343-1346.
80. Gauttier, V., Pichard, V., Aubert, D., Kaeppel, C., Schmidt, M., Ferry, N., and Conchon, S., No tumour-initiating risk associated with scAAV transduction in newborn rat liver. Gene Ther, 2013. 20(7): p. 779-784.
81. Bell, P., Wang, L., Lebherz, C., Flieder, D.B., Bove, M.S., Wu, D., Gao, G.P., Wilson, J.M., and Wivel, N.A., No evidence for tumorigenesis of AAV vectors in a large-scale study in mice. Mol Ther, 2005. 12(2): p. 299-306.
82. Li, H., Malani, N., Hamilton, S.R., Schlachterman, A., Bussadori, G., Edmonson, S.E., Shah, R., Arruda, V.R., Mingozzi, F., Wright, J.F., Bushman, F.D., and High, K.A., Assessing the potential for AAV vector genotoxicity in a murine model. Blood, 2011. 117(12): p. 3311-3319.
83. Niemeyer, G.P., Herzog, R.W., Mount, J., Arruda, V.R., Tillson, D.M., Hathcock, J., Van Ginkel, F.W., High, K.A., and Lothrop, C.D., Jr., Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy. Blood, 2009. 113(4): p. 797-806.
84. Kaeppel, C., Beattie, S.G., Fronza, R., Van Logtenstein, R., Salmon, F., Schmidt, S., Wolf, S., Nowrouzi, A., Glimm, H., Von Kalle, C., Petry, H., Gaudet, D., and Schmidt, M., A largely random AAV integration profile after LPLD gene therapy. Nat Med, 2013. 19(7): p. 889-891.
85. Gil-Farina, I., Fronza, R., Kaeppel, C., Lopez-Franco, E., Ferreira, V., D'avola, D., Benito, A., Prieto, J., Petry, H., Gonzalez-Aseguinolaza, G., and Schmidt, M., Recombinant AAV Integration Is Not Associated With Hepatic Genotoxicity in Nonhuman Primates and Patients. Mol Ther, 2016. 24(6): p. 1100-1105.
86. Chandler, R.J., Lafave, M.C., Varshney, G.K., Trivedi, N.S., Carrillo-Carrasco, N., Senac, J.S., Wu, W., Hoffmann, V., Elkahloun, A.G., Burgess, S.M., and Venditti, C.P., Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J Clin Invest, 2015. 125(2): p. 870-880.
87. Nault, J.C., Datta, S., Imbeaud, S., Franconi, A., Mallet, M., Couchy, G., Letouze, E., Pilati, C., Verret, B., Blanc, J.F., Balabaud, C., Calderaro, J., Laurent, A., Letexier, M., Bioulac-Sage, P., Calvo, F., and Zucman-Rossi, J., Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet, 2015. 47(10): p. 1187-1193.
88. Logan, G.J., Dane, A.P., Hallwirth, C.V., Smyth, C.M., Wilkie, E.E., Amaya, A.K., Zhu, E., Khandekar, N., Ginn, S.L., Liao, S.H.Y., Cunningham, S.C., Sasaki, N., Cabanes-Creus, M., Tam, P.P.L., Russell, D.W., Lisowski, L., and Alexander, I.E., Identification of liver-specific enhancer-promoter activity in the 3' untranslated region of the wild-type AAV2 genome. Nat Genet, 2017. 49(8): p. 1267-1273.
89. George, L.A., Ragni, M.V., Samelson-Jones, B.J., Cuker, A., Runoski, A.R., Cole, G., Wright, F., Chen, Y., Hui, D.J., Wachtel, K., Takefman, D., Couto, L.B., Reape, K.Z., Carr, M.E., Anguela, X.M., and Katherine A. High, M., Spk-8011: Preliminary Results from a Phase 1/2 Dose Escalation Trial of an Investigational AAV-Mediated Gene Therapy for Hemophilia A. Blood, 2017. 130(Suppl1): p. 604.
90. Mount, J.D., Herzog, R.W., Tillson, D.M., Goodman, S.A., Robinson, N., Mccleland, M.L., Bellinger, D., Nichols, T.C., Arruda, V.R., Lothrop, C.D., Jr., and High, K.A., Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy. Blood, 2002. 99(8): p. 2670-2676.
91. Finn, J.D., Ozelo, M.C., Sabatino, D.E., Franck, H.W., Merricks, E.P., Crudele, J.M., Zhou, S., Kazazian, H.H., Lillicrap, D., Nichols, T.C., and Arruda, V.R., Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy. Blood, 2010. 116(26): p. 5842-5848.
92. Van Dijk, K., Van Der Bom, J.G., Bax, K.N., Van Der Zee, D.C., and Van Den Berg, M.H., Use of implantable venous access devices in children with severe hemophilia: benefits and burden. Haematologica, 2004. 89(2): p. 189-194.
93. Hay, C.R., Dimichele, D.M., and International Immune Tolerance, S., The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood, 2012. 119(6): p. 1335-1344.
94. Arruda, V.R., Doshi, B.S., and Samelson-Jones, B.J., Novel approaches to hemophilia therapy: successes and challenges. Blood, 2017. 130(21): p. 2251-2256.
95. Stanford, S., Pink, R., Creagh, D., Clark, A., Lowe, G., Curry, N., Pasi, J., Perry, D., Fong, S., Hayes, G., Chandrakumaran, K., and Rangarajan, S., Adenovirus-associated antibodies in UK cohort of hemophilia patients: A seroprevalence study of the presence of adenovirus-associated virus vector-serotypes AAV5 and AAV8 neutralizing activity and antibodies in patients with hemophilia A. Res Pract Thromb Haemost, 2019. 3(2): p. 261-267.
96. Monteilhet, V., Saheb, S., Boutin, S., Leborgne, C., Veron, P., Montus, M.F., Moullier, P., Benveniste, O., and Masurier, C., A 10 patient case report on the impact of plasmapheresis upon neutralizing factors against adeno-associated virus (AAV) types 1, 2, 6, and 8. Mol Ther, 2011. 19(11): p. 2084-2091.
97. Unzu, C., Hervas-Stubbs, S., Sampedro, A., Mauleon, I., Mancheno, U., Alfaro, C., De Salamanca, R.E., Benito, A., Beattie, S.G., Petry, H., Prieto, J., Melero, I., and Fontanellas, A., Transient and intensive pharmacological immunosuppression fails to improve AAV-based liver gene transfer in non-human primates. J Transl Med, 2012. 10: p. 122.
98. Nathwani, A.C., Reiss, U., Tuddenham, E., Chowdary, P., Mcintosh, J., Riddell, A., Pie, J., Mahlangu, J.N., Recht, M., and Shen, Y.-M., Adeno-Associated Mediated Gene Transfer for Hemophilia B: 8 Year Follow up and Impact of Removing" Empty Viral Particles" on Safety and Efficacy of Gene Transfer. 2018, Am Soc Hematology.
99. Meliani, A., Boisgerault, F., Hardet, R., Marmier, S., Collaud, F., Ronzitti, G., Leborgne, C., Costa Verdera, H., Simon Sola, M., Charles, S., Vignaud, A., Van Wittenberghe, L., Manni, G., Christophe, O., Fallarino, F., Roy, C., Michaud, A., Ilyinskii, P., Kishimoto, T.K., and Mingozzi, F., Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration. Nat Commun, 2018. 9(1): p. 4098.
100. Machin, N., Ragni, M.V., and Smith, K.J., Gene therapy in hemophilia A: a cost-effectiveness analysis. Blood Adv, 2018. 2(14): p. 1792-1798.
101. Lang, J.F., Toulmin, S.A., Brida, K.L., Eisenlohr, L.C., and Davidson, B.L., Standard screening methods underreport AAV-mediated transduction and gene editing. Nat Commun, 2019. 10(1): p. 3415.
102. Skinner, M.W., Nugent, D., Wilton, P., O'mahony, B., Dolan, G., O'hara, J., and Berntorp, E., Achieving the unimaginable: Health equity in haemophilia. Haemophilia, 2020. 26(1): p. 17-24.
103. Lisowski, L., Dane, A.P., Chu, K., Zhang, Y., Cunningham, S.C., Wilson, E.M., Nygaard, S., Grompe, M., Alexander, I.E., and Kay, M.A., Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature, 2014. 506(7488): p. 382-386.
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Doshi, B. S., Arruda, V. R. and Arruda, V. R. (2020) “Guest Editor: G. Castaman GENE THERAPY FOR HEMOPHILIA: FACTS AND QUANDARIES IN THE 21ST CENTURY: GENE THERAPY FOR HEMOPHILIA”, Mediterranean Journal of Hematology and Infectious Diseases, 12(1), p. e2020069. doi: 10.4084/mjhid.2020.069.
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