Login Register Cart 0
Generic placeholder image

Current Gene Therapy

Editor-in-Chief

ISSN (Print): 1566-5232
ISSN (Online): 1875-5631

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

Characteristics of BAY 2599023 in the Current Treatment Landscape of Hemophilia A Gene Therapy

Author(s): Steven W. Pipe*, Valder R. Arruda, Claudia Lange, Stephen Kitchen, Hermann Eichler and Samuel Wadsworth

Volume 23, Issue 2, 2023

Published on: 28 November, 2022

Page: [81 - 95] Pages: 15

DOI: 10.2174/1566523222666220914105729

Price: $65

Abstract

Hemophilia A, a single gene disorder leading to deficient Factor VIII (FVIII), is a suitable candidate for gene therapy. The aspiration is for single administration of a genetic therapy that would allow the production of endogenous FVIII sufficient to restore hemostasis and other biological processes. This would potentially result in reliable protection from bleeding and its associated physical and emotional impacts. Gene therapy offers the possibility of a clinically relevant improvement in disease phenotype and transformational improvement in quality of life, including an opportunity to engage in physical activities more confidently. Gene therapy products for hemophilia A in advanced clinical development use adeno-associated viral (AAV) vectors and a codon-optimized B-domain deleted FVIII transgene. However, the different AAV-based gene therapies have distinct design features, such as choice of vector capsid, enhancer and promoter regions, FVIII transgene sequence and manufacturing processes. These, in turn, impact patient eligibility, safety and efficacy. Ideally, gene therapy technology for hemophilia A should offer bleed protection, durable FVIII expression, broad eligibility and limited response variability between patients, and long-term safety. However, several limitations and challenges must be overcome. Here, we introduce the characteristics of the BAY 2599023 (AAVhu37.hFVIIIco, DTX 201) gene therapy product, including the low prevalence in the general population of anti-AAV-hu37 antibodies, as well as other gene therapy AAV products and approaches. We will examine how these can potentially meet the challenges of gene therapy, with the ultimate aim of improving the lives of patients with hemophilia A.

Keywords: (6–8 keywords): AAV vector, manufacturing, hemophilia A, gene therapy, treatment landscape, factor VIII, BAY 2599023

« Previous
Graphical Abstract

[1]
Kuzmin DA, Shutova MV, Johnston NR, et al. The clinical landscape for AAV gene therapies. Nat Rev Drug Discov 2021; 20(3): 173-4.
[http://dx.doi.org/10.1038/d41573-021-00017-7] [PMID: 33495615]
[2]
Papanikolaou E, Bosio A. The promise and the hope of gene therapy. Front Genome Ed 2021; 3: 618346.
[http://dx.doi.org/10.3389/fgeed.2021.618346] [PMID: 34713249]
[3]
Perrin GQ, Herzog RW, Markusic DM. Update on clinical gene therapy for hemophilia. Blood 2019; 133(5): 407-14.
[http://dx.doi.org/10.1182/blood-2018-07-820720] [PMID: 30559260]
[4]
Srivastava A, Santagostino E, Dougall A, et al. WFH guidelines for the management of hemophilia. Haemophilia 2020; 26(S6): 1-158.
[5]
Hermans C, Noone D, Benson G, et al. Hemophilia treatment in 2021: Choosing the“optimal” treatment using an integrative, patient-oriented approach to shared decision-making between patients and clinicians. Blood Rev 2022; 52: 100890.
[http://dx.doi.org/10.1016/j.blre.2021.100890] [PMID: 34736780]
[6]
Valentino LA. Blood-induced joint disease: The pathophysiology of hemophilic arthropathy. J Thromb Haemost 2010; 8(9): 1895-902.
[http://dx.doi.org/10.1111/j.1538-7836.2010.03962.x] [PMID: 20586922]
[7]
Davari M, Gharibnaseri Z, Ravanbod R, Sadeghi A. Health status and quality of life in patients with severe hemophilia A: A cross-sectional survey. Hematol Rep 2019; 11(2): 7894.
[http://dx.doi.org/10.4081/hr.2019.7894] [PMID: 31285808]
[8]
Iorio A, Stonebraker JS, Chambost H, et al. Data and Demographics Committee of the World Federation of Hemophilia. Establishing the prevalence and prevalence at birth of hemophilia in males: A meta-analytic approach using national registries. Ann Intern Med 2019; 171(8): 540-6.
[http://dx.doi.org/10.7326/M19-1208] [PMID: 31499529]
[9]
National Hemophilia Association. Available from: https://www.hemophilia.org/bleeding-disorders-a-z/types/hemophilia-a [Accessed 17 November, 2021].
[10]
Samuelson Bannow B, Recht M, Négrier C, et al. Factor VIII: Long-established role in haemophilia A and emerging evidence beyond haemostasis. Blood Rev 2019; 35: 43-50.
[http://dx.doi.org/10.1016/j.blre.2019.03.002] [PMID: 30922616]
[11]
Bhat V, Olmer M, Joshi S, et al. Vascular remodeling underlies rebleeding in hemophilic arthropathy. Am J Hematol 2015; 90(11): 1027-35.
[http://dx.doi.org/10.1002/ajh.24133] [PMID: 26257191]
[12]
Starke RD, Ferraro F, Paschalaki KE, et al. Endothelial von Willebrand factor regulates angiogenesis. Blood 2011; 117(3): 1071-80.
[http://dx.doi.org/10.1182/blood-2010-01-264507] [PMID: 21048155]
[13]
Larson EA, Taylor JA. Factor VIII plays a direct role in osteoblast development. Blood 2017; 130 (Suppl. 1): 3661.
[14]
Mannucci PM. Hemophilia therapy: The future has begun. Haematologica 2020; 105(3): 545-53.
[http://dx.doi.org/10.3324/haematol.2019.232132] [PMID: 32060150]
[15]
Berntorp E, Shapiro AD. Modern haemophilia care. Lancet 2012; 379(9824): 1447-56.
[http://dx.doi.org/10.1016/S0140-6736(11)61139-2] [PMID: 22456059]
[16]
Gringeri A, Lundin B, Von MacKensen S, Mantovani L, Mannucci PM. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost 2011; 9(4): 700-10.
[http://dx.doi.org/10.1111/j.1538-7836.2011.04214.x] [PMID: 21255253]
[17]
Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357(6): 535-44.
[http://dx.doi.org/10.1056/NEJMoa067659] [PMID: 17687129]
[18]
Yan S, Maro GS, Desai V, Simpson ML. A real-world analysis of commonly prescribed FVIII products based on U.S. medical charts: Consumption and bleeding outcomes in hemophilia A patients. J Manag Care Spec Pharm 2020; 26(10): 1258-65.
[http://dx.doi.org/10.18553/jmcp.2020.20199] [PMID: 32820685]
[19]
Astermark J, Petrini P, Tengborn L, Schulman S, Ljung R, Berntorp E. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized. Br J Haematol 1999; 105(4): 1109-13.
[http://dx.doi.org/10.1046/j.1365-2141.1999.01463.x] [PMID: 10554828]
[20]
Nijdam A, Foppen W, van der Schouw YT, Mauser-Bunschoten EP, Schutgens REG, Fischer K. Long-term effects of joint bleeding before starting prophylaxis in severe haemophilia. Haemophilia 2016; 22(6): 852-8.
[http://dx.doi.org/10.1111/hae.12959] [PMID: 27396935]
[21]
Hassan S, Cannavò A, Gouw SC, Rosendaal FR, van der Bom JG. Factor VIII products and inhibitor development in previously treated patients with severe or moderately severe hemophilia A: A systematic review. J Thromb Haemost 2018; 16(6): 1055-68.
[http://dx.doi.org/10.1111/jth.14124] [PMID: 29665204]
[22]
Vézina C, Carcao M, Infante-Rivard C, et al. Association of Hemophilia Clinic Directors of Canada and of the Canadian Association of Nurses in Hemophilia Care. Incidence and risk factors for inhibitor development in previously untreated severe haemophilia A patients born between 2005 and 2010. Haemophilia 2014; 20(6): 771-6.
[http://dx.doi.org/10.1111/hae.12479] [PMID: 25039669]
[23]
Walsh CE, Soucie JM, Miller CH. United States Hemophilia Treatment Center Network. Impact of inhibitors on hemophilia a mortality in the United States. Am J Hematol 2015; 90(5): 400-5.
[http://dx.doi.org/10.1002/ajh.23957] [PMID: 25616111]
[24]
De la Corte-Rodriguez H, Rodriguez-Merchan EC, Alvarez-Roman MT, Martin-Salces M, Martinoli C, Jimenez-Yuste V. The value of HEAD-US system in detecting subclinical abnormalities in joints of patients with hemophilia. Expert Rev Hematol 2018; 11(3): 253-61.
[http://dx.doi.org/10.1080/17474086.2018.1435269] [PMID: 29383965]
[25]
Zanon E, Pasca S. Intracranial haemorrhage in children and adults with haemophilia A and B: A literature review of the last 20 years. Blood Transfus 2019; 17(5): 378-84.
[PMID: 30747705]
[26]
Aledort L, Mannucci PM, Schramm W, Tarantino M. Factor VIII replacement is still the standard of care in haemophilia A. Blood Transfus 2019; 17(6): 479-86.
[PMID: 31846611]
[27]
Thornburg C, Duncan N. Treatment adherence in hemophilia. Patient Prefer Adherence 2017; 11: 1677-86.
[http://dx.doi.org/10.2147/PPA.S139851] [PMID: 29033555]
[28]
Walsh CE, Valentino LA. Factor VIII prophylaxis for adult patients with severe haemophilia A: Results of a US survey of attitudes and practices. Haemophilia 2009; 15(5): 1014-21.
[http://dx.doi.org/10.1111/j.1365-2516.2009.02036.x] [PMID: 19493018]
[29]
Valentino LA, Pipe SW, Collins PW, et al. Association of peak factor VIII levels and area under the curve with bleeding in patients with haemophilia A on every third day pharmacokinetic‐guided prophylaxis. Haemophilia 2016; 22(4): 514-20.
[http://dx.doi.org/10.1111/hae.12905] [PMID: 26930418]
[30]
Nathwani AC. Gene therapy for hemophilia. Hematology (Am Soc Hematol Educ Program) 2019; 2019(1): 1-8.
[http://dx.doi.org/10.1182/hematology.2019000007] [PMID: 31808868]
[31]
Mendell JR, Al-Zaidy SA, Rodino-Klapac LR, et al. Current clinical applications of in vivo gene therapy with AAVs. Mol Ther 2021; 29(2): 464-88.
[http://dx.doi.org/10.1016/j.ymthe.2020.12.007] [PMID: 33309881]
[32]
Srivastava A, Lusby EW, Berns KI. Nucleotide sequence and organization of the adeno-associated virus 2 genome. J Virol 1983; 45(2): 555-64.
[http://dx.doi.org/10.1128/jvi.45.2.555-564.1983] [PMID: 6300419]
[33]
Xie Q, Bu W, Bhatia S, et al. The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy. Proc Natl Acad Sci USA 2002; 99(16): 10405-10.
[http://dx.doi.org/10.1073/pnas.162250899] [PMID: 12136130]
[34]
Gao G, Vandenberghe LH, Alvira MR, et al. Clades of Adeno-associated viruses are widely disseminated in human tissues. J Virol 2004; 78(12): 6381-8.
[http://dx.doi.org/10.1128/JVI.78.12.6381-6388.2004] [PMID: 15163731]
[35]
Grimm D, Lee JS, Wang L, et al. In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J Virol 2008; 82(12): 5887-911.
[http://dx.doi.org/10.1128/JVI.00254-08] [PMID: 18400866]
[36]
Georg-Fries B, Biederlack S, Wolf J, Zur Hausen H. Analysis of proteins, helper dependence, and seroepidemiology of a new human parvovirus. Virology 1984; 134(1): 64-71.
[http://dx.doi.org/10.1016/0042-6822(84)90272-1] [PMID: 6200995]
[37]
Ellis BL, Hirsch ML, Barker JC, Connelly JP, Steininger RJ III, Porteus MH. A survey of ex vivo/in vitro transduction efficiency of mammalian primary cells and cell lines with nine natural adeno-associated virus (AAV1-9) and one engineered adeno-associated virus serotype. Virol J 2013; 10(1): 74.
[http://dx.doi.org/10.1186/1743-422X-10-74] [PMID: 23497173]
[38]
Podsakoff G, Wong KK Jr, Chatterjee S. Efficient gene transfer into nondividing cells by adeno-associated virus-based vectors. J Virol 1994; 68(9): 5656-66.
[http://dx.doi.org/10.1128/jvi.68.9.5656-5666.1994] [PMID: 8057446]
[39]
Wang D, Tai PWL, Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov 2019; 18(5): 358-78.
[http://dx.doi.org/10.1038/s41573-019-0012-9] [PMID: 30710128]
[40]
Patel U, Boucher M, de Léséleuc L, Visintini S. Voretigene Neparvovec: An Emerging Gene Therapy for the Treatment of Inherited Blindness CADTH Issues in Emerging Health Technologies. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health 2016; pp. 1-11.
[41]
Maguire AM, Russell S, Chung DC, et al. Durability of voretigene neparvovec for biallelic RPE65-mediated inherited retinal disease: Phase 3 results at 3 and 4 years. Ophthalmology 2021; 128(10): 1460-8.
[http://dx.doi.org/10.1016/j.ophtha.2021.03.031] [PMID: 33798654]
[42]
Mendell JR, Al-Zaidy SA, Lehman KJ, et al. Five-year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol 2021; 78(7): 834-41.
[http://dx.doi.org/10.1001/jamaneurol.2021.1272] [PMID: 33999158]
[43]
Shahani T, Covens K, Lavend’homme R, et al. Human liver sinusoidal endothelial cells but not hepatocytes contain factor VIII. J Thromb Haemost 2014; 12(1): 36-42.
[http://dx.doi.org/10.1111/jth.12412] [PMID: 24118899]
[44]
Stel HV, van der Kwast TH, Veerman ECI. Detection of factor VIII/coagulant antigen in human liver tissue. Nature 1983; 303(5917): 530-2.
[http://dx.doi.org/10.1038/303530a0] [PMID: 6406906]
[45]
Sonntag F, Bleker S, Leuchs B, Fischer R, Kleinschmidt JA. Adeno-associated virus type 2 capsids with externalized VP1/VP2 trafficking domains are generated prior to passage through the cytoplasm and are maintained until uncoating occurs in the nucleus. J Virol 2006; 80(22): 11040-54.
[http://dx.doi.org/10.1128/JVI.01056-06] [PMID: 16956943]
[46]
Martino AT, Basner-Tschakarjan E, Markusic DM, et al. Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsid-specific CD8+ T cells. Blood 2013; 121(12): 2224-33.
[http://dx.doi.org/10.1182/blood-2012-10-460733] [PMID: 23325831]
[47]
Mingozzi F, Schüttrumpf J, Arruda VR, et al. Improved hepatic gene transfer by using an adeno-associated virus serotype 5 vector. J Virol 2002; 76(20): 10497-502.
[http://dx.doi.org/10.1128/JVI.76.20.10497-10502.2002] [PMID: 12239326]
[48]
Grimm D, Pandey K, Nakai H, Storm TA, Kay MA. Liver transduction with recombinant adeno-associated virus is primarily restricted by capsid serotype not vector genotype. J Virol 2006; 80(1): 426-39.
[http://dx.doi.org/10.1128/JVI.80.1.426-439.2006] [PMID: 16352567]
[49]
Rumachik NG, Malaker SA, Poweleit N, et al. Methods matter: Standard production platforms for recombinant AAV produce chemically and functionally distinct vectors. Mol Ther Methods Clin Dev 2020; 18: 98-118.
[http://dx.doi.org/10.1016/j.omtm.2020.05.018] [PMID: 32995354]
[50]
Summerford C, Samulski RJ. Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions. J Virol 1998; 72(2): 1438-45.
[http://dx.doi.org/10.1128/JVI.72.2.1438-1445.1998] [PMID: 9445046]
[51]
Pillay S, Meyer NL, Puschnik AS, et al. An essential receptor for adeno-associated virus infection. Nature 2016; 530(7588): 108-12.
[http://dx.doi.org/10.1038/nature16465] [PMID: 26814968]
[52]
Nonnenmacher M, Weber T. Intracellular transport of recombinant adeno-associated virus vectors. Gene Ther 2012; 19(6): 649-58.
[http://dx.doi.org/10.1038/gt.2012.6] [PMID: 22357511]
[53]
Watakabe A, Ohtsuka M, Kinoshita M, et al. Comparative analyses of adeno-associated viral vector serotypes 1, 2, 5, 8 and 9 in marmoset, mouse and macaque cerebral cortex. Neurosci Res 2015; 93: 144-57.
[http://dx.doi.org/10.1016/j.neures.2014.09.002] [PMID: 25240284]
[54]
Paulk NK, Pekrun K, Zhu E, et al. Bioengineered AAV capsids with combined high human liver transduction in vivo and unique humoral seroreactivity. Mol Ther 2018; 26(1): 289-303.
[http://dx.doi.org/10.1016/j.ymthe.2017.09.021] [PMID: 29055620]
[55]
Castaman G, Matino D. Hemophilia A and B: molecular and clinical similarities and differences. Haematologica 2019; 104(9): 1702-9.
[http://dx.doi.org/10.3324/haematol.2019.221093] [PMID: 31399527]
[56]
Gitschier J, Wood WI, Goralka TM, et al. Characterization of the human factor VIII gene. Nature 1984; 312(5992): 326-30.
[http://dx.doi.org/10.1038/312326a0] [PMID: 6438525]
[57]
Yoshitake S, Schach BG, Foster DC, Davie EW, Kurachi K. Complete nucleotide sequences of the gene for human factor IX (antihemophilic factor B). Biochemistry 1985; 24(14): 3736-50.
[http://dx.doi.org/10.1021/bi00335a049] [PMID: 2994716]
[58]
Toole JJ, Knopf JL, Wozney JM, et al. Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 1984; 312(5992): 342-7.
[http://dx.doi.org/10.1038/312342a0] [PMID: 6438528]
[59]
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(1): 107-15.
[http://dx.doi.org/10.1182/blood-2005-12-5115] [PMID: 16522813]
[60]
Wood WI, Capon DJ, Simonsen CC, et al. Expression of active human factor VIII from recombinant DNA clones. Nature 1984; 312(5992): 330-7.
[http://dx.doi.org/10.1038/312330a0] [PMID: 6438526]
[61]
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.
[http://dx.doi.org/10.1089/hum.1996.7.17-2101] [PMID: 8934224]
[62]
Vehar GA, Keyt B, Eaton D, et al. Structure of human factor VIII. Nature 1984; 312(5992): 337-42.
[http://dx.doi.org/10.1038/312337a0] [PMID: 6438527]
[63]
Toole JJ, Pittman DD, Orr EC, Murtha P, Wasley LC, Kaufman RJ. A large region (approximately equal to 95 kDa) of human factor VIII is dispensable for in vitro procoagulant activity. Proc Natl Acad Sci USA 1986; 83(16): 5939-42.
[http://dx.doi.org/10.1073/pnas.83.16.5939] [PMID: 3016730]
[64]
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(11): 2925-35.
[http://dx.doi.org/10.1182/blood.V81.11.2925.2925] [PMID: 8499631]
[65]
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(1): 19-27.
[http://dx.doi.org/10.1111/j.1432-1033.1995.tb20776.x] [PMID: 7556150]
[66]
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(17): 3335-44.
[http://dx.doi.org/10.1182/blood-2012-10-462200] [PMID: 23426947]
[67]
Almstedt A, Brandt J, Gray E, et al. Structural and functional characteristics of the B-domain-deleted recombinant factor VIII protein, r-VIII SQ. Thromb Haemost 2001; 85(1): 93-100.
[http://dx.doi.org/10.1055/s-0037-1612910] [PMID: 11204595]
[68]
Brown HC, Zakas PM, George SN, Parker ET, Spencer HT, Doering CB. Target-cell-directed bioengineering approaches for gene therapy of hemophilia A. Mol Ther Methods Clin Dev 2018; 9: 57-69.
[http://dx.doi.org/10.1016/j.omtm.2018.01.004] [PMID: 29552578]
[69]
Yan C, Costa RH, Darnell JE Jr, Chen JD, Van Dyke TA. Distinct positive and negative elements control the limited hepatocyte and choroid plexus expression of transthyretin in transgenic mice. EMBO J 1990; 9(3): 869-78.
[http://dx.doi.org/10.1002/j.1460-2075.1990.tb08184.x] [PMID: 1690125]
[70]
Gorski K, Carneiro M, Schibler U. Tissue-specific in vitro transcription from the mouse albumin promoter. Cell 1986; 47(5): 767-76.
[http://dx.doi.org/10.1016/0092-8674(86)90519-2] [PMID: 3779841]
[71]
Okuyama T, Huber RM, Bowling W, et al. Liver-directed gene therapy: A retroviral vector with a complete LTR and the ApoE enhancer-alpha 1-antitrypsin promoter dramatically increases expression of human alpha 1-antitrypsin in vivo. Hum Gene Ther 1996; 7(5): 637-45.
[http://dx.doi.org/10.1089/hum.1996.7.5-637] [PMID: 8845389]
[72]
Wright J. Product-related impurities in clinical-grade recombinant AAV vectors: Characterization and risk assessment. Biomedicines 2014; 2(1): 80-97.
[http://dx.doi.org/10.3390/biomedicines2010080] [PMID: 28548061]
[73]
Luo Y, Frederick A, Martin JM, et al. AAVS1-targeted plasmid integration in AAV producer cell lines. Hum Gene Ther Methods 2017; 28(3): 124-38.
[http://dx.doi.org/10.1089/hgtb.2016.158] [PMID: 28504553]
[74]
Martin J, Frederick A, Luo Y, et al. Generation and characterization of adeno-associated virus producer cell lines for research and preclinical vector production. Hum Gene Ther Methods 2013; 24(4): 253-69.
[http://dx.doi.org/10.1089/hgtb.2013.046] [PMID: 23848282]
[75]
Clark KR, Voulgaropoulou F, Fraley DM, Johnson PR. Cell lines for the production of recombinant adeno-associated virus. Hum Gene Ther 1995; 6(10): 1329-41.
[http://dx.doi.org/10.1089/hum.1995.6.10-1329] [PMID: 8590738]
[76]
Urabe M, Ding C, Kotin RM. Insect cells as a factory to produce adeno-associated virus type 2 vectors. Hum Gene Ther 2002; 13(16): 1935-43.
[http://dx.doi.org/10.1089/10430340260355347] [PMID: 12427305]
[77]
Gorovits B, Azadeh M, Buchlis G, et al. Evaluation of the humoral response to adeno-associated virus-based gene therapy modalities using total antibody assays. AAPS J 2021; 23(6): 108.
[http://dx.doi.org/10.1208/s12248-021-00628-3] [PMID: 34529177]
[78]
Wobus CE, Hügle-Dörr B, Girod A, Petersen G, Hallek M, Kleinschmidt JA. Monoclonal antibodies against the adeno-associated virus type 2 (AAV-2) capsid: Epitope mapping and identification of capsid domains involved in AAV-2-cell interaction and neutralization of AAV-2 infection. J Virol 2000; 74(19): 9281-93.
[http://dx.doi.org/10.1128/JVI.74.19.9281-9293.2000] [PMID: 10982375]
[79]
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.
[http://dx.doi.org/10.1089/hum.2017.150] [PMID: 28835127]
[80]
FDA. Human gene therapy for hemophilia: Guidance for industry. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/human-gene-therapy-hemophilia [Accessed January, 2022].
[81]
Miesbach W, O’Mahony B, Key NS, Makris M. How to discuss gene therapy for haemophilia? A patient and physician perspective. Haemophilia 2019; 25(4): hae.13769.
[http://dx.doi.org/10.1111/hae.13769] [PMID: 31115117]
[82]
Nakai H, Storm TA, Kay MA. Recruitment of single-stranded recombinant adeno-associated virus vector genomes and intermolecular recombination are responsible for stable transduction of liver in vivo. J Virol 2000; 74(20): 9451-63.
[http://dx.doi.org/10.1128/JVI.74.20.9451-9463.2000] [PMID: 11000214]
[83]
Nakai H, Yant SR, Storm TA, Fuess S, Meuse L, Kay MA. Extrachromosomal recombinant adeno-associated virus vector genomes are primarily responsible for stable liver transduction in vivo. J Virol 2001; 75(15): 6969-76.
[http://dx.doi.org/10.1128/JVI.75.15.6969-6976.2001] [PMID: 11435577]
[84]
Stanger BZ. Cellular homeostasis and repair in the mammalian liver. Annu Rev Physiol 2015; 77(1): 179-200.
[http://dx.doi.org/10.1146/annurev-physiol-021113-170255] [PMID: 25668020]
[85]
Mingozzi F, Maus MV, Hui DJ, et al. CD8+ T-cell responses to adeno-associated virus capsid in humans. Nat Med 2007; 13(4): 419-22.
[http://dx.doi.org/10.1038/nm1549] [PMID: 17369837]
[86]
George LA, Ragni MV, Rasko JEJ, et al. Long-term follow-up of the first in human intravascular delivery of AAV for gene transfer: AAV2-hFIX16 for severe hemophilia B. Mol Ther 2020; 28(9): 2073-82.
[http://dx.doi.org/10.1016/j.ymthe.2020.06.001] [PMID: 32559433]
[87]
Meliani A, Boisgerault F, Hardet R, et al. Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration. Nat Commun 2018; 9(1): 4098.
[http://dx.doi.org/10.1038/s41467-018-06621-3] [PMID: 30291246]
[88]
Johansson BP, Shannon O, Björck L. IdeS: a bacterial proteolytic enzyme with therapeutic potential. PLoS One 2008; 3(2): e1692.
[http://dx.doi.org/10.1371/journal.pone.0001692] [PMID: 18301769]
[89]
Leborgne C, Barbon E, Alexander JM, et al. IgG-cleaving endopeptidase enables in vivo gene therapy in the presence of anti-AAV neutralizing antibodies. Nat Med 2020; 26(7): 1096-101.
[http://dx.doi.org/10.1038/s41591-020-0911-7] [PMID: 32483358]
[90]
Elmore ZC, Oh DK, Simon KE, Fanous MM, Asokan A. Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme. JCI Insight 2020; 5(19): e139881.
[http://dx.doi.org/10.1172/jci.insight.139881] [PMID: 32941184]
[91]
Bertin B, Veron P, Leborgne C, et al. Capsid-specific removal of circulating antibodies to adeno-associated virus vectors. Sci Rep 2020; 10(1): 864.
[http://dx.doi.org/10.1038/s41598-020-57893-z] [PMID: 31965041]
[92]
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(1): 47-55.
[http://dx.doi.org/10.1038/s41587-020-0741-7] [PMID: 33199875]
[93]
Nathwani AC, Reiss U, Tuddenham E, et al. 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. Blood 2018; 132 (Suppl. 1): 491.
[http://dx.doi.org/10.1182/blood-2018-99-118334]
[94]
Kepa S, Horvath B, Reitter-Pfoertner S, et al. Parameters influencing FVIII pharmacokinetics in patients with severe and moderate haemophilia A. Haemophilia 2015; 21(3): 343-50.
[http://dx.doi.org/10.1111/hae.12592] [PMID: 25582282]
[95]
Zhu J, Huang X, Yang Y. The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice. J Clin Invest 2009; 119(8): 2388-98.
[http://dx.doi.org/10.1172/JCI37607] [PMID: 19587448]
[96]
Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA. Nature 2000; 408(6813): 740-5.
[http://dx.doi.org/10.1038/35047123] [PMID: 11130078]
[97]
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(6): 763-74.
[http://dx.doi.org/10.1182/blood.2019004625] [PMID: 33067633]
[98]
Lange AM, Altynova ES, Nguyen GN, Sabatino DE. Overexpression of factor VIII after AAV delivery is transiently associated with cellular stress in hemophilia A mice. Mol Ther Methods Clin Dev 2016; 3: 16064.
[http://dx.doi.org/10.1038/mtm.2016.64] [PMID: 27738645]
[99]
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(3): 342-7.
[http://dx.doi.org/10.1038/nm1358] [PMID: 16474400]
[100]
Morales L, Gambhir Y, Bennett J, Stedman HH. Broader implications of progressive liver dysfunction and lethal sepsis in two boys following systemic high-dose AAV. Mol Ther 2020; 28(8): 1753-5.
[http://dx.doi.org/10.1016/j.ymthe.2020.07.009] [PMID: 32710826]
[101]
Philippidis A. Fourth boy dies in clinical trial of Astellas’ AT132. Hum Gene Ther 2021; 32(19-20): 1008-10.
[http://dx.doi.org/10.1089/hum.2021.29182.bfs] [PMID: 34662231]
[102]
Philippidis A. After third death, Audentes’ AT132 remains on clinical hold. Hum Gene Ther 2020; 31(17-18): 908-10.
[http://dx.doi.org/10.1089/hum.2020.29133.bfs] [PMID: 32945722]
[103]
Zolotukhin I, Markusic DM, Palaschak B, Hoffman BE, Srikanthan MA, Herzog RW. Potential for cellular stress response to hepatic factor VIII expression from AAV vector. Mol Ther Methods Clin Dev 2016; 3: 16063.
[http://dx.doi.org/10.1038/mtm.2016.63] [PMID: 27738644]
[104]
Gil-Farina I, Fronza R, Kaeppel C, et al. Recombinant AAV integration is not associated with hepatic genotoxicity in nonhuman primates and patients. Mol Ther 2016; 24(6): 1100-5.
[http://dx.doi.org/10.1038/mt.2016.52] [PMID: 26948440]
[105]
Donsante A, Miller DG, Li Y, et al. AAV vector integration sites in mouse hepatocellular carcinoma. Science 2007; 317(5837): 477.
[http://dx.doi.org/10.1126/science.1142658] [PMID: 17656716]
[106]
Schmidt M, Foster GR, Coppens M, et al. Liver safety case report from the phase 3 HOPE-B gene therapy trial in adults with hemophilia B. Res Pract Thromb Haemost 2021; 5(Suppl 2)https://abstracts.isth.org/abstract/liver-safety-case-report-from-the-phase-3-hope-b-gene-therapy-trial-in-adults-with-hemophilia-b/
[107]
Marlar RA, Strandberg K, Shima M, Adcock DM. Clinical utility and impact of the use of the chromogenic vs. one‐stage factor activity assays in haemophilia A and B. Eur J Haematol 2020; 104(1): 3-14.
[http://dx.doi.org/10.1111/ejh.13339] [PMID: 31606899]
[108]
Tiefenbacher S, Gosselin R, Kitchen S. Factor activity assays for monitoring extended half-life FVIII and factor IX replacement therapies. Semin Thromb Hemost 2017; 43(3): 331-7.
[http://dx.doi.org/10.1055/s-0037-1598058] [PMID: 28264199]
[109]
Rangarajan S, Walsh L, Lester W, et al. AAV5-factor VIII gene transfer in severe hemophilia A. N Engl J Med 2017; 377(26): 2519-30.
[http://dx.doi.org/10.1056/NEJMoa1708483] [PMID: 29224506]
[110]
Rosen S, Tiefenbacher S, Robinson M, et al. Activity of transgene-produced B-domain-deleted factor VIII in human plasma following AAV5 gene therapy. Blood 2020; 136(22): 2524-34.
[http://dx.doi.org/10.1182/blood.2020005683] [PMID: 32915950]
[111]
Greig JA, Nordin JML, White JW, et al. Optimized adeno-associated viral-mediated human factor VIII gene therapy in cynomolgus macaques. Hum Gene Ther 2018; 29(12): 1364-75.
[http://dx.doi.org/10.1089/hum.2018.080] [PMID: 29890905]
[112]
Greig JA, Wang Q, Reicherter AL, et al. Characterization of adeno-associated viral vector-mediated human factor VIII gene therapy in hemophilia A mice. Hum Gene Ther 2017; 28(5): 392-402.
[http://dx.doi.org/10.1089/hum.2016.128] [PMID: 28056565]
[113]
Pipe S, Leebeek FWG, Ferreira V, Sawyer EK, Pasi J. Clinical considerations for capsid choice in the development of liver-targeted AAV-based gene transfer. Mol Ther Methods Clin Dev 2019; 15: 170-8.
[http://dx.doi.org/10.1016/j.omtm.2019.08.015] [PMID: 31660419]
[114]
Wang L, Wang H, Bell P, et al. Systematic evaluation of AAV vectors for liver directed gene transfer in murine models. Mol Ther 2010; 18(1): 118-25.
[http://dx.doi.org/10.1038/mt.2009.246] [PMID: 19861950]
[115]
Pipe SW, Ferrante F, Reis M, Wiegmann S, Lange C, Braun M. First-in-human gene therapy study of AAVhu37 capsid vector technology in severe Hemophilia A-BAY 2599023 has broad patient eligibility and stable and sustained long-term expression of FVIII. Blood 2020; 136 (Suppl. 1): 44-5.
[116]
Wang L, Bell P, Somanathan S, et al. Comparative study of liver gene transfer with AAV vectors based on natural and engineered AAV capsids. Mol Ther 2015; 23(12): 1877-87.
[http://dx.doi.org/10.1038/mt.2015.179] [PMID: 26412589]
[117]
Pipe SW, Hay C, Sheehan J, et al. Evolution of AAV vector gene therapy is ongoing in hemophilia. Will the unique features of BAY 2599023 address the outstanding needs? Res Pract Thromb Haemost 2021; 5(Suppl 2)https://abstracts.isth.org/abstract/evolution-of-aav-vector-gene-therapy-is-ongoing-in-hemophilia-will-the-unique-features-of-bay-2599023-address-the-outstanding-needs/
[118]
Pipe SW, Sheehan JP, Coppens M, et al. First-in-human dose-finding study of AAVhu37 vector-based gene therapy: BAY 2599023 has stable and sustained expression of FVIII over 2 years. Am Soc Hematol 2021; 136 (Suppl. 1): 3971.
[119]
Long BR, Sandza K, Holcomb J, et al. The impact of pre-existing immunity on the non-clinical pharmacodynamics of AAV5-based gene therapy. Mol Ther Methods Clin Dev 2019; 13: 440-52.
[http://dx.doi.org/10.1016/j.omtm.2019.03.006] [PMID: 31193016]
[120]
Rajavel K, Ayash-Rashkovsky M, Tang Y, Gangadharan B, de la Rosa M, Ewenstein B. Co-prevalence of pre-existing immunity to different serotypes of adeno-associated virus (AAV) in adults with hemophilia. Blood 2019; 134 (Suppl. 1): 3349.
[http://dx.doi.org/10.1182/blood-2019-123666]
[121]
Pasi KJ, Laffan M, Rangarajan S, et al. Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A. Haemophilia 2021; 27(6): 947-56.
[http://dx.doi.org/10.1111/hae.14391] [PMID: 34378280]
[122]
Ozelo M, Mahlangu J, Pasi KJ, et al. Efficacy and safety of valoctocogene roxaparvovec adeno-associated virus gene transfer for severe hemophilia A: Results from the phase 3 GENEr8-1 trial. ISTH 2021.
[123]
BioMarin. BioMarin receives Complete Response Letter (CRL) from FDA for valoctocogene roxaparvovec gene therapy for severe hemophilia A. 2020.
[124]
Pipe SW, Ozelo M, Kenet G. Relationship between endogenous, transgene FVIII expression and bleeding events following valoctocogene roxaparvovec gene transfer for severe hemophilia A: A post-hoc analysis of the GENEr8-1 phase 3 trial. Am Soc Hematol 2021; 138 (Suppl. 1): 3972.
[125]
Monahan PE, Négrier C, Tarantino M, Valentino LA, Mingozzi F. Emerging immunogenicity and genotoxicity considerations of adeno-associated virus vector gene therapy for hemophilia. J Clin Med 2021; 10(11): 2471.
[http://dx.doi.org/10.3390/jcm10112471] [PMID: 34199563]
[126]
Visweshwar N, Harrington TJ, Leavitt AD. Updated results of the Alta study, a phase 1/2 study of giroctocogene fitelparvovec (PF-07055480/SB-525) gene therapy in adults with severe hemophilia A. Am Soc Hematol 2021; 138 (Suppl. 1): 564.
[http://dx.doi.org/10.1182/blood-2021-148651]
[127]
Sangamo. Sangamo therapeutics reports recent business and clinical highlights and third quarter 2021 financial results. 2021. Available from: https://investor.sangamo.com/news-releases/news-release-details/sangamo-therapeutics-reports-recent-business-and-clinical
[128]
George LA, Monahan PE, Eyster ME, et al. Multiyear factor VIII expression after AAV gene transfer for hemophilia A. N Engl J Med 2021; 385(21): 1961-73.
[http://dx.doi.org/10.1056/NEJMoa2104205] [PMID: 34788507]
[129]
Sullivan SKB, Barrett JC, Drelich DA, et al. Preliminary results from a phase 1/2 clinical trial of gene therapy for hemophilia A. Haemophilia 2021; 27 (Suppl. 2): 18-181.
[130]
Veselinovic MG, Gilam A, Ross A, et al. Preclinical development of ASC-618, an advanced human factor VIII gene therapy vector for the treatment of hemophilia A: Results from FRG-KO humanized liver mice, C57Bl/6 mice and cynomolgus monkeys. Mol Ther 2020; 28(4): 167-8.
[131]
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.
[http://dx.doi.org/10.1086/595830] [PMID: 19133809]
[132]
Cantore A, Naldini L. WFH State‐of‐the‐art paper 2020: In vivo lentiviral vector gene therapy for haemophilia. Haemophilia 2021; 27 (Suppl. 3): 122-5.
[http://dx.doi.org/10.1111/hae.14056] [PMID: 32537776]
[133]
World Health Organization. HIV/AIDS. 2021. Available from: https://www.who.int/data/gho/data/themes/hiv-aids [Accessed 26 November, 2021].
[134]
Fu Y, Foden JA, Khayter C, et al. High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells. Nat Biotechnol 2013; 31(9): 822-6.
[http://dx.doi.org/10.1038/nbt.2623] [PMID: 23792628]
[135]
Luo S, Li Z, Dai X, et al. CRISPR/Cas9-mediated in vivo genetic correction in a mouse model of hemophilia A. Front Cell Dev Biol 2021; 9: 672564.
[http://dx.doi.org/10.3389/fcell.2021.672564] [PMID: 34485274]
[136]
Miesbach W, Klamroth R. The patient experience of gene therapy for hemophilia: Qualitative interviews with trial patients. Patient Prefer Adherence 2020; 14: 767-70.
[http://dx.doi.org/10.2147/PPA.S239810] [PMID: 32368018]
[137]
Machin N, Ragni MV, Smith KJ. Gene therapy in hemophilia A: A cost-effectiveness analysis. Blood Adv 2018; 2(14): 1792-8.
[http://dx.doi.org/10.1182/bloodadvances.2018021345] [PMID: 30042145]
[138]
Konkle BA, Coffin D, Pierce GF, et al. World federation of hemophilia gene therapy registry. Haemophilia 2020; 26(4): 563-4.
[http://dx.doi.org/10.1111/hae.14015] [PMID: 32462720]
[139]
Sidonio RF Jr, Pipe SW, Callaghan MU, Valentino LA, Monahan PE, Croteau SE. Discussing investigational AAV gene therapy with hemophilia patients: A guide. Blood Rev 2021; 47: 100759.
[http://dx.doi.org/10.1016/j.blre.2020.100759] [PMID: 33183859]
[140]
Aiyegbusi OL, Macpherson K, Elston L, et al. Patient and public perspectives on cell and gene therapies: A systematic review. Nat Commun 2020; 11(1): 6265.
[http://dx.doi.org/10.1038/s41467-020-20096-1] [PMID: 33293538]
[141]
Pipe SW. Delivering on the promise of gene therapy for haemophilia. Haemophilia 2021; 27(S3): 114-21.
[http://dx.doi.org/10.1111/hae.14027] [PMID: 32490590]

Rights & Permissions Print Cite
Article Metrics
2
© 2024 Bentham Science Publishers | Privacy Policy