Clinical Gene Transfer Studies for Hemophilia A

The recent advances in gene transfer technology have expedited the development of gene therapy for the treatment of hemophilia A. Three different U.S. Food and Drug Administration-approved phase I clinical trials had been initiated using different gene therapy approaches each with their own advantages and limitations. In the first gene therapy trial for hemophilia A, a non-viral approach was being explored for patients with severe hemophilia A using ex vivo transfected dermal fibroblast expressing B-domain-deleted factor VIII (BDD-FVIII). There were no serious adverse events and some patients appeared to have experienced fewer bleeding episodes with very low levels of FVIII near baseline. In the second trial, onco-retroviral vectors expressing BDD-FVIII were injected by peripheral intravenous infusion in adult patients suffering from severe hemophilia A. The procedure was safe and in some patients FVIII-transduced cells were detectable in the peripheral blood for more than a year. Although no sustained FVIII expression was detectable, occasional modest changes in FVIII levels were apparent, and in some cases a reduced bleeding frequency occurred compared with historical rates. In another trial, one patient suffering from severe hemophilia A has been treated with a high-capacity (or gutless) adenoviral vector expressing full-length FVIII, which appeared to have resulted in 1% of normal FVIII levels for several months. However, a transient inflammatory response with hematologic and liver abnormalities was observed. In conclusion, although modest improvements in clinical end points have been detected in some patients in these early phase I trials, further improvements in gene delivery technologies are warranted to bring hemophilia A gene therapy one step closer to reality.

Hemophilia A - factor VIII - gene therapy

REFERENCES

• 1 Ragni M V. Hemophilia gene transfer: comparison with conventional protein replacement therapy.  Semin Thromb Hemost. 2004;  30 239-248
• 2 Roth D A, Tawa Jr N E, O'Brien J M, Treco D A, Selden R F. Factor VIII Transkaryotic Therapy Study Group. Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A.  N Engl J Med. 2001;  344 1735-1742
• 3 Selden R F, Skoskiewicz M J, Howie K B, Russell P S, Goodman H M. Implantation of genetically engineered fibroblasts into mice: implications for gene therapy.  Science. 1987;  236 714-718
• 4 Selden R F, Skokiewicz M, Russell P S, Goodman H M. Regulation of insulin-gene expression: implications for gene therapy.  N Engl J Med. 1987;  317 1067-1076
• 5 Heartlein M W, Roman V A, Jiang J-L et al.. Long-term production and delivery of human growth hormone in vivo.  Proc Natl Acad Sci USA. 1994;  91 10967-10971
• 6 Toole J J, Pittman D D, Orr E C, Murtha P, Wasley L, Kaufman R J. 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 5939-5942
• 7 Eaton D L, Wood W I, Eaton D et al.. Construction and characterization of an active factor VIII variant lacking the central one-third of the molecule.  Biochemistry. 1986;  25 8343-8347
• 8 Roth D A, Treco D A. A phase 1 study of nonviral ex vivo factor VIII gene transfer in 12 severe hemophilia A study subjects. Paper presented at: Sixth NHF Workshop on Gene Therapies for Hemophilia; April 26 2003 Salk Institute La Jolla, CA; 2003: 30
• 9 Miller D G, Stamatoyannopoulos G. Gene therapy for hemophilia.  N Engl J Med. 2001;  344 1782-1784
• 10 Petrini P. What factors should influence the dosage and interval of prophylactic treatment in patients with severe haemophilia A and B?.  Haemophilia. 2001;  7 99-102
• 11 Hacein-Bey-Abina S, von Kalle C, Schmidt M et al.. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency.  N Engl J Med. 2003;  348 255-256
• 12 Van Damme A, Chuah M KL, Collen D, VandenDriessc T. Onco-retroviral and lentiviral vector-based gene therapy for hemophilia: preclinical studies.  Semin Thromb Hemost. 2004;  30 185-196
• 13 Marshall E. Gene therapy on trial.  Science. 2000;  288 951-957
• 14 Arruda V R, Fields P A, Milner R et al.. Lack of germline transmission of vector sequences following systemic administration of recombinant AAV-2 vector in males.  Mol Ther. 2001;  4 586-592
• 15 Pastore L, Morral N, Zhou H et al.. Use of a liver-specific promoter reduces immune response to the transgene in adenoviral vectors.  Hum Gene Ther. 1999;  10 1773-1781
• 16 Zhang W W, Josephs S F, Zhou J et al.. Development and application of a minimal-adenoviral vector system for gene therapy of hemophilia A.  Thromb Haemost. 1999;  82 562-571
• 17 Raper S E, Yudkoff M, Chirmule N et al.. A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency.  Hum Gene Ther. 2002;  13 163-175
• 18 Glader B, Kay M A, Hutchison S A et al.. A phase I trial of AAV-mediated, liver-directed gene transfer for hemophilia B. Paper presented at: Sixth NHF Workshop on Gene Therapies for Hemophilia; April 26, 2003 Salk Institute La Jolla, CA; 2003: 31
• 19 White G C. Clinical trial results with MaxAdFVIII, a gutless adenovirus vector driving liver-specific expression of full-length factor VIII. Paper presented at: Sixth NHF Workshop on Gene Therapies for Hemophilia April 26, 2003 Salk Institute La Jolla, CA; 2003
• 20 VandenDriessche T, Collen D, Chuah M K. Gene therapy for the hemophilias.  J Thromb Haemost. 2003;  1 1550-1558
• 21 Chuah M KL, Damme A V, Zwinnen H et al.. Long-term persistence of human bone marrow stromal cells transduced with factor VIII-retroviral vectors and production of therapeutic levels of human factor VIII in nonmyeloablated immunodeficient mice.  Hum Gene Ther. 2000;  11 729-738
• 22 Dwarki V J, Belloni P, Nijar T et al.. Gene therapy for hemophilia A: production of therapeutic levels of human factor VIII in vivo in mice.  Proc Natl Acad Sci USA. 1995;  92 1023-1027
• 23 Powell J S, Ragni M V, White II G C et al.. Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion.  Blood. 2003;  102 2038-2045
• 24 Greengard J S, Jolly D J. Animal testing of retroviral-mediated gene therapy for factor VIII deficiency.  Thromb Haemost. 1999;  82 555-561
• 25 McCormack J E, Edwards W, Sensintaffer J et al.. Factors affecting long-term expression of a secreted transgene product after intravenous administration of a retroviral vector.  Mol Ther. 2001;  3 516-525
• 26 Roehl H H, Leibbrandt M E, Greengard J S et al.. 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 2529-2540
• 27 Lothrop C, Niemeyer G P, Dufresne M et al.. Treatment of canine hemophilia A by direct infusion of retroviral vector expressing the human FVIII cDNA.  Mol Ther. 2000;  5 S289 , (abst)
• 28 Greengard J S, Bodner M, McCormack J et al.. Systemic expression of human factor VIII from peripheral retroviral delivery in rabbits and dogs.  Blood. 1997;  90(suppl 1) 240a , (abst)
• 29 VandenDriessche T, Vanslembrouck V, Goovaerts I et al.. Long-term expression of human coagulation factor VIII and correction of hemophilia A after in vivo retroviral gene transfer in factor VIII-deficient mice.  Proc Natl Acad Sci USA. 1999;  96 10379-10384
• 30 VandenDriessche T. Challenges and progress in gene therapy for hemophilia A.  Blood. 2003;  102 1938-1939
• 31 Xu L, Gao C, Sands M S et al.. 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 3924-3932
• 32 White G C. Gene therapy in hemophilia: clinical trials update.  Thromb Haemost. 2001;  86 172-177
• 33 Thorrez L, VandenDriessche T, Collen D, Chuah M KL. Preclinical gene therapy studies for hemophilia using adenoviral vectors.  Semin Thromb Hemost. 2004;  30 173-184
• 34 Zhang W W, Josephs S F, Zhou J et al.. Development and application of a minimal-adenoviral vector system for gene therapy of hemophilia A.  Thromb Haemost. 1999;  82 562-571
• 35 Balague C, Zhou J, Dai Y et al.. 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;  95 820-828
• 36 Fang B, Andreason G, Hariharan M et al.. Pre-clinical efficacy and safety studies of a gutless adenovirus vector (MAXADFVIII) for treatment of haemophilia A.  Thromb Haemost. 2001;  86 OC2490 , (abst)
• 37 Chuah M K, Schiedner G, Thorrez L et al.. Therapeutic factor VIII levels and negligible toxicity in mouse and dog models of hemophilia A following gene therapy with high-capacity adenoviral vectors.  Blood. 2003;  101 1734-1743
• 38 Mannucci P M, Tuddenham E G. The hemophilias-from royal genes to gene therapy.  N Engl J Med. 2001;  344 1773-1779
• 39 Yamada T, Iwasaki Y, Tada H et al.. Nanoparticles for the delivery of genes and drugs to human hepatocytes.  Nat Biotechnol. 2003;  21 885-890