2003; baxter - Supplements - Haematologica

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120T. VandenDriessche et al.ed to further explore the full potential of lentiviralvectors for hemophilia A gene therapy.HC-Ad vectorsAdenoviral vectors can transduce dividing andnon-dividing cells and are by far the most efficientvectors for hepatic gene delivery. 35 The adenoviralvector genome remains episomal, implyingthat the risk of neoplastic transformation dueto insertional mutagenesis is low. Whereas early-generationadenoviral vectors still containmost viral genes which contribute to inflammatoryresponses, toxicity and short-term transgeneexpression, HC-Ad vectors retain only the necessarycis-acting elements that are required for generatinginfectious vector particles during vectorproduction and the transgene of interest. 35 HC-Ad vectors expressing B-domain deleted humanor canine FVIII from different liver-specific promoterswere injected intravenously into hemophilicFVIII-deficient mice which resulted inphysiologic levels of canine or human FVIII (VandenDriesscheet al, unpublished observations).These results underscore the potential usefulnessof HC-Ad for hemophilia A gene therapy. However,the induction of neutralizing antibodiesdirected against the human or canine xenoproteinsprecluded stable phenotypic correction.ConclusionsThe ideal gene therapy vector for hemophilia Ais not yet available but significant progress hasbeen made in further improving viral vectortechnology for FVIII gene delivery. Proof-of-concepthas recently been established demonstratingthat hemophilia A could be cured by genetherapy in a clinically relevant animal model thatmimics the cognate human disease. 21 This wasaccomplished by intravenous injection of oncoretroviralvectors expressing FVIII into neonatalhemophilic mice. Although these findings mayultimately pave the way towards potential genetherapy for pediatric hemophilia A, clinical trialsin children can only commence once safety hasbeen established in adults or perhaps in childrensuffering from a lethal disease, for which notreatment is currently available. The limitationof onco-retroviral vector mediated gene transferin dividing hepatocytes, could be overcome byusing either lentiviral or HC-Ad vectors, whichresulted in efficient hepatic gene transfer in adultmice. Using HC-Ad vectors, physiologic FVIIIexpression levels could be achieved in hemophilicmice. Follow-up studies in hemophilic mice anddogs are required to further evaluate the potentialof these vectors for gene therapy.The induction of inhibitory antibodies followinggene therapy may be related to several confoundingvariables including the type of vectorused, the purity of the vector preparation, thepromoter used to drive FVIII expression, the siteof administration, the transduced cell types(APC) or the underlying genetic defect and otherhost factors. Whether gene therapy wouldincrease or decrease the likelihood of inhibitorformation compared to protein replacementtherapy is one of the important questions thatstill needs to be addressed. Continuous productionof high levels FVIII in situ following genetherapy may actually induce immune tolerancereminiscent of current immune tolerizationstrategies by repeated high dose clotting factoradministration. Alternatively, gene transfer tonaive patients could evoke the same or even amore potent immune response to FVIII. A majorconcern is that the use of viral vectors expressingcoagulation factors or that impurities in the vectorpreparations may provide immunologicaldanger signals that may facilitate inhibitor formation.36 In addition, gene transfer may result inthe presentation of endogenously synthesizedFVIII–derived peptides in the context of MHCclass I molecules potentially resulting in CTLresponses that could eliminate the FVIII-engineeredtarget cells. The secreted FVIII protein thatis produced in vivo may also be presented in thecontext of MHC class II as in the case of infusedclotting factors. It is not clear whether gene therapycould break tolerance in patients that are tolerantto FVIII and whether inhibitors can be suppressedonce they occur following gene therapy.Since many adult hemophilia patients have aninfectious or inflammatory disease, complexinteractions can influence the therapeutic efficacyof the gene therapy procedure or the propensityfor inhibitor formation and caution is warrantednot to exacerbate these underlying conditions.Despite the tremendous progress in the fieldover the past few years many questions remainlargely unexplored. Extensive gene therapy studiesin preclinical hemophilia models are neededto anticipate the possible outcome in patientsand to increase the overall efficiency of the variousgene therapy strategies while further improvingtheir safety. The development of hemophiliagene therapy will undoubtedly continue to contributeto a better understanding of vector-hostinteractions that will benefit the entire field ofgene therapy. The results from the preclinicalstudies in hemophilic animal models indicatethat the simultaneous development of differentstrategies is likely to bring a permanent cure forhemophilia one step closer to reality.AcknowledgmentsThe authors wish to acknowledge Dr. Schiedner,Dr. Kochanek, Dr. Follenzi, Dr. Naldini, Dr. Berneman,Dr. Ory, Dr. Mulligan, Dr. Saint-Remy, Dr.Kazazian, Dr. Lillicrap, Dr. De Geest Mr. Thorrez,Mrs. Vanslembrouck, Ms. Gillijns, Mrs. Vanderhaegen,Mr. Lenjou Mrs. Johnston and Mrs. Hertelfor their valuable contributions.References1. Chuah MK, Collen D, VandenDriessche T. Gene therapyfor hemophilia: hopes and hurdles. Crit Rev OncolHematol 1998; 28:153-71.haematologica vol. 88(supplement n. 12):september <strong>2003</strong>
IV International Workshop on Immune Tolerance in Hemophilia 1212. Chuah MK, Collen D, VandenDriessche T. Gene therapyfor hemophilia. J Gene Med 2001; 3:3-20.3. VandenDriessche T, Collen D, Chuah MK. Viral vectormediatedgene therapy for hemophilia. Curr Gene Ther2001; 1:301-15.4. Miller AD, Miller DG, Garcia JV, Lynch CM. Use ofretroviral vectors for gene transfer and expression.Methods Enzymol 1993; 217:581-99.5. Miller AD. Retroviral vectors. Curr Top MicrobiolImmunol 1992; 158:1-24.6. Anderson WF. Human gene therapy. Nature 1998; 392:25-30.7. Cornetta K, Morgan RA, Gillio A, Sturm S, Baltrucki L,O'Reilly R, et al. No retroviremia or pathology in longtermfollow-up of monkeys exposed to a murineamphotropic retrovirus. Hum Gene Ther 1991; 2:215-9.8. Anderson WF, McGarrity GJ, Moen RC. Report to theNIH Recombinant DNA Advisory Committee onmurine replication-competent retrovirus (RCR) assays(February 17, 1993). Hum Gene Ther 1993; 4:311-21.9. Donahue RE, Kessler SW, Bodine D, McDonagh K,Dunbar C, Goodman S, et al. Helper virus induced Tcell lymphoma in nonhuman primates after retroviralmediated gene transfer. J Exp Med 1992; 176:1125-35.10. Hoeben RC, van der Jagt RC, Schoute F, van Tilburg NH,Verbeet MP, Briet E, et al. Expression of functional factorVIII in primary human skin fibroblasts after retrovirus-mediatedgene transfer. J Biol Chem 1990; 265:7318-23.11. Israel DI, Kaufman RJ. Retroviral-mediated transfer andamplification of a functional human factor VIII gene.Blood 1990; 75:1074-80.12. Lynch CM, Israel DI, Kaufman RJ, Miller AD. Sequencesin the coding region of clotting factor VIII act as dominantinhibitors of RNA accumulation and protein production.Hum Gene Ther 1993; 4:259-72.13. Chuah MK, Vandendriessche T, Morgan RA. Developmentand analysis of retroviral vectors expressinghuman factor VIII as a potential gene therapy for hemophiliaA. Hum Gene Ther 1995; 6:1363-77.14. Hoeben RC, Fallaux FJ, Cramer SJ, van den WollenbergDJ, van Ormondt H, Briet E, et al. Expression of theblood-clotting factor-VIII cDNA is repressed by a transcriptionalsilencer located in its coding region. Blood1995; 85:2447-54.15. Koeberl DD, Halbert CL, Krumm A, Miller AD.Sequences within the coding regions of clotting factorVIII and CFTR block transcriptional elongation. HumGene Ther 1995; 6:469-79.16. Fallaux FJ, Hoeben RC, Cramer SJ, van den WollenbergDJ, Briet E, van Ormondt H, et al. The human clottingfactor VIII cDNA contains an autonomously replicatingsequence consensus- and matrix attachment region-likesequence that binds a nuclear factor, represses heterologousgene expression, and mediates the transcriptionaleffects of sodium butyrate. Mol Cell Biol 1996; 16:4264-72.17. Dwarki VJ, Belloni P, Nijjar T, Smith J, Couto L, RabierM, Clift S, Berns A, Cohen LK. Gene therapy for hemophiliaA: production of therapeutic levels of human factorVIII in vivo in mice. Proc Natl Acad Sci USA 1995;92:1023-7.18. Krall W, Kohn DB. Expression levels by retroviral vectorsbased upon the N2 and the MFG backbones. Gene Ther1996; 3:365.19. Palmiter RD, Sandgren EP, Avarbock MR, Allen DD,Brinster RL. Heterologous introns can enhance expressionof transgenes in mice. Proc Natl Acad Sci USA1991; 88:478-82.20. Hamer DH, Leder P. Splicing and the formation of stableRNA. Cell 1979; 18:1299-302.21. VandenDriessche T, Vanslembrouck V, Goovaerts I,Zwinnen H, Vanderhaeghen ML, Collen D, et al. Longtermexpression of human coagulation factor VIII andcorrection of hemophilia A after in vivo retroviral genetransfer in factor VIII- deficient mice. Proc Natl Acad SciUSA 1999; 96:10379-84.22. VandenDriessche T, Naldini L, Collen D, Chuah MK.Oncoretroviral and lentiviral vector-mediated gene therapy.Methods Enzymol 2002; 346:573-89.23. Kreuz W, Becker S, Lenz E, Martinez Saguer I, EscuriolaEttingshausen C, Funk M, et al. Factor VIII inhibitors inpatients with hemophilia A: epidemiology of inhibitordevelopment and induction of immune tolerance forfactor VIII. Semin Thromb Hemost 1995; 21:382-9.24. Pittman DD, Alderman EM, Tomkinson KN, Wang JH,Giles AR, Kaufman RJ. Biochemical, immunological,and in vivo functional characterization of B-domaindeletedfactor VIII. Blood 1993; 81:2925-35.25. Qian J, Borovok M, Bi L, Kazazian HH Jr, Hoyer LW.Inhibitor antibody development and T cell response tohuman factor VIII in murine hemophilia A. ThrombHaemost 1999; 81:240-4.26. Lewis PF, Emerman M. Passage through mitosis isrequired for oncoretroviruses but not for the humanimmunodeficiency virus. J Virol 1994; 68:510-6.27. Naldini L. Lentiviruses as gene transfer agents for deliveryto non-dividing cells. Curr Opin Biotechnol 1998;9: 457-63.28. Park F, Ohashi K, Chiu W, Naldini L, Kay MA. Efficientlentiviral transduction of liver requires cell cycling invivo. Nat Genet 2000; 24:49-52.29. Kafri T, van Praag H, Ouyang L, Gage FH, Verma IM. Apackaging cell line for lentivirus vectors. J Virol 1999;73:576-84.30. Zufferey R, Nagy D, Mandel RJ, Naldini L, Trono D.Multiply attenuated lentiviral vector achieves efficientgene delivery in vivo. Nat Biotechnol 1997; 15:871-5.31. Chinnasamy D, Chinnasamy N, Enriquez MJ, Otsu M,Morgan RA, Candotti F. Lentiviral-mediated gene transferinto human lymphocytes: role of HIV-1 accessoryproteins. Blood 2000; 96:1309-16.32. Park F, Ohashi K, Kay MA. Therapeutic levels of humanfactor VIII and IX using HIV-1-based lentiviral vectorsin mouse liver. Blood 2000; 96:1173-6.33. Follenzi A, Ailles LE, Bakovic S, Geuna M, Naldini L.Gene transfer by lentiviral vectors is limited by nucleartranslocation and rescued by HIV-1 pol sequences. NatGenet 2000; 25:217-22.34. Pastore L, Morral N, Zhou H, Garcia R, Parks RJ,Kochanek S, et al. Use of a liver-specific promoterreduces immune response to the transgene in adenoviralvectors. Hum Gene Ther 1999; 10:1773-81.35. Kochanek S. Development of high-capacity adenoviralvectors for gene therapy. Thromb Haemost 1999; 82:547-51.36. Matzinger P. An innate sense of danger. SeminImmunol 1998; 10:399-415.37. Chao H, Walsh CE. Induction of tolerance to humanfactor VIII in mice. Blood 2001; 97:3311-2.haematologica vol. 88(supplement n. 12):september <strong>2003</strong>
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