Gene Therapy in Hemophilia: Clinical Trials Update

Summary

Disorders caused by inborn genetic errors have been a primary target for treatment by gene transfer. Hemophilia A and B have been considered especially important targets because the genes for factor VIII and IX are well characterized, levels of factor VIII and IX do not require complex regulation, small increases in factor level would have significant clinical benefits, good clinical and laboratory tests of efficacy exist, and excellent animal models of hemophilia are available. Four clinical trials of gene transfer in hemophilia, two in hemophilia A and two in hemophilia B, are currently underway or have been completed and two other trials have been approved. The collective interim results from these trials indicate that the current approaches and doses are safe and that low levels of expression are detected. These studies support the continued development of gene transfer as a potential treatment option for hemophilia.

Key words

Hemophilia - gene therapy - retrovirus - adeno-associated virus - adenovirus

• References

• 1 Kaufman RJ. Advances toward gene therapy for hemophilia at the millennium. Hum Gene Ther 1999; 10: 2091-107.
• 2 Kay MA. Hepatic gene therapy for haemophilia B. Haemophilia 1998; 4: 389-92.
• 3 Connelly S, Kaleko M. Haemophilia A gene therapy. Haemophilia 1998; 4: 380-8.
• 4 Herzog RW, High KA. Problems and prospects in gene therapy for hemophilia. Curr Opin Hematol 1998; 5: 321-6.
• 5 Zhang Z, Eriksson M, Blomback M, Anvret M. A new approach to gene therapy. Blood Coagul Fibrinolysis 1997; 8: S39-42.
• 6 Eisensmith RC, Woo SL. Viral vector-mediated gene therapy for hemophilia B. Thromb Haemost 1997; 78: 24-30.
• 7 Verma IM, Somia N. Gene therapy – promises, problems and prospects. Nature 1997; 389: 239-42.
• 8 Qiu X, Lu D, Zhou J, Wang J, Yang J, Meng P, Hsueh JL. Implantation of autologous skin fibroblast genetically modified to secrete clotting factor IX partially corrects the hemorrhagic tendencies in two hemophilia B patients. Chin Med J 1996; 109: 832-9.
• 9 Hsueh JL. Clinical protocol of human gene transfer for hemophilia B. Hum Gene Ther 1992; 3: 543-52.
• 10 Roth DA, Tawa NE, O’Brien J, Levine JD, Furie B, Furie BC, Proper J, Roman VA, Sabine ZM, Lamsa JC, Gunter KC, Phillips CW, Savioli NA, Treco DA, Selden RF. Non-viral gene transfer of blood coagulation factor VIII in patients with severe hemophilia A. Blood 2000; 96: 590a (abstr.).
• 11 DePolo NJ, Harkleroad CE, Bodner M, Watt AT, Anderson CG, Greengard JS, Murthy KK, Dubensky Jr TW, Jolly DJ. The resistance of retroviral vectors produced from human cells to serum inactivation in vivo and in vitro is primate species dependent. J Virol 1999; 73: 6708-14.
• 12 Greengard JS, Jolly DJ. Animal testing of retroviral-mediated gene therapy for factor VIII deficiency. Thromb Haemost 1999; 82: 555-61.
• 13 Kazazian Jr HH. An estimated frequency of endogenous insertional mutations in humans. Nat Genet 1999; 22: 130.
• 14 Roehl HH, Leibbrandt ME, Greengard JS, Kamantigue E, Glass WG, Giedlin M, Boekelheide K, Johnson DE, Jolly DJ, Sajjadi NC. Analysis of testes and semen from rabbits treated by intravenous injection with a retroviral vector encoding the human factor VIII gene: No evidence of germ line transduction. Hum Gene Ther 2000; 11: 2529-40.
• 15 Herzog RW, Hagstrom JN, Kung SH, Tai SJ, Wilson JM, Fisher KJ, High KA. Stable gene transfer and expression of human blood coagulation factor IX after intramuscular injection of recombinant adeno-associated virus. Proc Natl Acad Sci USA 1997; 94: 5804-9.
• 16 Herzog RW, Yang EY, Couto LB, Hagstrom JN, Elwell D, Fields PA, Burton M, Bellinger DA, Read MS, Brinkhous KM, Podsakoff GM, Nichols TC, Kurtzman GJ, High KA. Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector. Nat Med 1999; 5: 56-63.
• 17 Herzog RW, High KA. Adeno-associated virus-mediated gene transfer of factor IX for treatment of hemophilia B by gene therapy. Thromb Haemost 1999; 82: 540-6.
• 18 Kay MA, Manno CS, Ragni MV, Larson PJ, Couto LB, McClelland A, Glader B, Chew AJ, Tai SJ, Herzog RW, Arruda V, Johnson F, Scallan C, Skarsgard E, Flake AW, High KA. Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat Genet 2000; 24: 257-61.
• 19 Manno CS, Glader B, Ragni MV, Thompson AR, Costa F, Chew AJ, Herzog RW, Arruda V, Couto LB, McClelland A, Johnson F, Flake A, Skarsgard E, Armstrong E, Kay MA, High KA. A phase I trial of AAV-mediated muscle directed gene transfer for hemophilia B. Blood 2000; 96: 801a (abstr.).
• 20 Zhang WW, Josephs SF, Zhou J, Fang X, Alemany R, Balague C, Dai Y, Ayares D, Prokopenko E, Lou YC, Sethi E, Hubert-Leslie D, Kennedy M, Ruiz L, Rockow-Magnone S. Development and application of a minimal-adenoviral vector system for gene therapy of hemophilia A. Thromb Haemost 1999; 82: 562-71.
• 21 Balague C, Zhou J, Dai Y, Alemany R, Josephs SF, Andreason G, Hariharan M, Sethi E, Prokopenko E, Jan HY, Lou YC, Hubert-Leslie D, Ruiz L, Zhang WW. Sustained high-level expression of full-length human factor VIII and restoration of clotting activity in hemophilic mice using a minimal adenovirus vector. Blood 2000; 95: 820-8.
• 22 Fang X, Zhang W-W, Sobol RE, Gomperts E, Thompson AR, Wong W, Kohn D, Rogers R, Fischer T, Nichols TC, Murthy KK, Cobb EK, Fahs S, Montgomery RR, White II G.. Studies in non-human primate and hemophilic dog models of a “gutless” adenovirus vector for treatment of hemophilia A. Blood 2000; 96: 428a (abstr.).
• 23 Nakai H, Ohashi K, Arruda V, McClelland A, Couto LB, Meuse L, Storm T, Drake MD, Manno CS, Glader B, High KA, Kay MA. A proposed rAAV-liver directed clinical trial for hemophilia B. Blood 2000; 96: 798a (abstr.).
• 24 Lozier JN, Metzger ME, Donahue RE, Morgan RA. Adenovirus-mediated expression of human coagulation factor IX in the rhesus macaque is associated with dose-limiting toxicity. Blood 1999; 94: 3968-75.
• 25 Gallo-Penn AM, Shirley PS, Andrews JL, Tinlin S, Webster S, Cameron C, Hough C, Notley C, Lillicrap D, Kaleko M, Connelly S. Systemic delivery of an adenoviral vector encoding canine factor VIII results in short-term phenotypic correction, inhibitor development, and biphasic liver toxicity in hemophilia A dogs. Blood 2001; 97: 107-13.
• 26 Sheridan PL, Bodner M, Lynn A, Phuong TK, DePolo NJ, de la Vega Jr DJ, O’Dea J, Nguyen K, McCormack JE, Driver DA, Townsend K, Ibanez CE, Sajjadi NC, Greengard JS, Moore MD, Respess J, Chang SM, Dubensky Jr TW, Jolly DJ, Sauter SL. Generation of retroviral packaging and producer cell lines for large-scale vector production and clinical application: Improved safety and high titer. Mol Ther 2000; 2: 262-75.
• 27 Pages JC, Loux N, Bellusci S, Farge D, Bennoun M, Vons C, Jouanneau J, Franco D, Briand P, Weber A. Hepatocyte growth factor expressed by a retrovirus-producing cell line enhances retroviral transduction of primary hepatocytes: implications for in vivo gene transfer. Biochem Biophys Res Commun 1996; 222: 726-31.
• 28 Nguyen TH, Pages JC, Farge D, Briand P, Weber A. Amphotropic retroviral vectors displaying hepatocyte growth factor-envelope fusion proteins improve transduction efficiency of primary hepatocytes. Hum Gene Ther 1998; 9: 2469-79.
• 29 Gao C, Jokerst R, Gondipalli P, Cai SR, Kennedy S, Ponder KP. Intramuscular injection of an adenoviral vector expressing hepatocyte growth factor facilitates hepatic transduction with a retroviral vector in mice. Hum Gene Ther 1999; 10: 911-22.
• 30 Naldini L, Blomer U, Gallay P, Ory D, Mulligan R, Gage FH, Verma IM, Trono D. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 1996; 272: 263-7.
• 31 Naldini L. In vivo gene delivery by lentiviral vectors. Thromb Haemost 1999; 82: 552-4.
• 32 Olsen JC. Gene transfer vectors derived from equine infectious anemia virus. Gene Ther 1998; 5: 1481-7.
• 33 Poeschla EM, Wong-Staal F, Looney DJ. Efficient transduction of nondividing human cells by feline immunodeficiency virus lentiviral vectors. Nat Med 1998; 4: 354-7.
• 34 Curran MA, Kaiser SM, Achacoso PL, Nolan GP. Efficient transduction of nondividing cells by optimized feline immunodeficiency virus vectors. Mol Ther 2000; 1: 31-8.
• 35 Russell DW, Miller AD. Foamy virus vectors. J Virol 1996; 70: 217-22.
• 36 Park F, Ohashi K, Kay MA. Therapeutic levels of human factor VIII and IX using HIV-1-based lentiviral vectors in mouse liver. Blood 2000; 96: 1173-6.
• 37 Chao H, Liu Y, Rabinowitz J, Li C, Samulski RJ, Walsh CE. Several log increase in therapeutic transgene delivery by distinct adeno-associated viral serotype vectors. Mol Ther 2000; 2: 619-23.
• 38 Pruchnic R, Cao B, Peterson ZQ, Xiao X, Li J, Samulski RJ, Epperly M, Huard J. The use of adeno-associated virus to circumvent the maturation-dependent viral transduction of muscle fibers. Hum Gene Ther 2000; 11: 521-36.
• 39 Dutheil N, Shi F, Dupressoir T, Linden RM. Adeno-associated virus site-specifically integrates into a muscle-specific DNA region. Proc Natl Acad Sci 2000; 97: 4862-6.
• 40 Fields PA, Kowalczyk DW, Arruda VR, Armstrong E, McCleland ML, Hagstrom JN, Pasi KJ, Ertl HC, Herzog RW, High KA. Role of vector in activation of T cell subsets in immune responses against the secreted transgene product factor IX. Mol Ther 2000; 1: 225-35.
• 41 Kochanek S, Clemens PR, Mitani K, Chen HH, Chan S, Caskey CT. A new adenoviral vector: Replacement of all viral coding sequences with 28 kb of DNA independently expressing both full-length dystrophin and beta-galactosidase. Proc Natl Acad Sci USA 1996; 93: 5731-6.
• 42 Morsy MA, Gu M, Motzel S, Zhao J, Lin J, Su Q, Allen H, Franlin L, Parks RJ, Graham FL, Kochanek S, Bett AJ, Caskey CT. An adenoviral vector deleted for all viral coding sequences results in enhanced safety and extended expression of a leptin transgene. Proc Natl Acad Sci USA 1998; 95: 7866-71.
• 43 Morral N, Parks RJ, Zhou H, Langston C, Schiedner G, Quinones J, Graham FL, Kochanek S, Beaudet AL. High doses of a helper-dependent adenoviral vector yield supraphysiological levels of alpha1-antitrypsin with negligible toxicity. Hum Gene Ther 1998; 9: 2709-16.
• 44 O’Neal WK, Zhou H, Morral N, Langston C, Parks RJ, Graham FL, Kochanek S, Beaudet AL. Toxicity associated with repeated administration of first-generation adenovirus vectors does not occur with a helper-dependent vector. Mol Med 2000; 6: 179-95.
• 45 Pastore L, Morral N, Zhou H, Garcia R, Parks RJ, Kochanek S, Graham FL, Lee B, Beaudet AL. Use of a liver-specific promoter reduces immune response to the transgene in adenoviral vectors. Hum Gene Ther 1999; 10: 1773-81.
• 46 Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, Horwitz MS, Crowell RL, Finberg RW. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 1997; 275: 1320-3.
• 47 Dechecchi MC, Tamanini A, Bonizzato A, Cabrini G. Heparan sulfate glycosaminoglycans are involved in adenovirus type 5 and 2-host cell interactions. Virology 2000; 268: 382-90.
• 48 Kirby I, Davison E, Beavil AJ, Soh CP, Wickham TJ, Roelvink PW, Kovesdi I, Sutton BJ, Santis G. Mutations in the DG loop of adenovirus type 5 fiber knob protein abolish high-affinity binding to its cellular receptor CAR. J Virol 1999; 73: 9508-14.
• 49 Kirby I, Davison E, Beavil AJ, Soh CP, Wickham TJ, Roelvink PW, Kovesdi I, Sutton BJ, Santis G. Identification of contact residues and definition of the CAR-binding site of adenovirus type 5 fiber protein. J Virol 2000; 74: 2804-13.
• 50 Verma IM. Gene therapy: The need for basic science. Mol Ther 2000; 2: 531.