2003; baxter - Supplements - Haematologica

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114D. LillicrapFundingThe author's hemophilia gene therapy studies arefunded by the Canadian Institutes of HealthResearch (grant MT-10912), the Canadian HemophiliaSociety and the Bayer/Canadian Blood ServicesPartnership Fund. DL is a Career Investigatorof the Heart and Stroke Foundation of Ontario andholds a Canada Research Chair in Molecular Hemostasis.References1. Powell JS, Ragni MV, White GC, Lusher J, Hillman-Wiseman C, Cole V, et al. Results from one year followup of a phase I trial of FVIII gene transfer for severehemophilia A using a retroviral construct administeredby peripheral intravenous infusion. Blood 2001; Suppl:a2896[abstract].2. Roth DA, Tawa NE, Jr, O'Brien JM, Treco DA, Selden RF.Nonviral transfer of the gene encoding coagulation factorVIII in patients with severe hemophilia A. N Engl JMed 2001; 344:1735-42.3. Kay MA, Manno CS, Ragni MV, Larson PJ, Couto LB,McClelland A, et al. Evidence for gene transfer andexpression of factor IX in haemophilia B patients treatedwith an AAV vector. Nat Genet 2000; 24:257-61.4. Graham FL. Adenovirus vectors for high-efficiency genetransfer into mammalian cells. Immunol Today 2000;21:426-8.5. Assessment of adenoviral vector safety and toxicity:report of the National Institutes of Health RecombinantDNA Advisory Committee. Hum Gene Ther 2002; 13:3-13.6. Lozier JN, Csako G, Mondoro TH, Krizek DM, MetzgerME, Costello R, et al. Toxicity of a first-generation adenoviralvector in rhesus macaques. Hum Gene Ther2002; 13:113-24.7. Morral N, O'Neal WK, Rice K, Leland MM, Piedra PA,Aguilar-Cordova E, et al. Lethal toxicity, severe endothelialinjury, and a threshold effect with high doses of anadenoviral vector in baboons. Hum Gene Ther 2002;13:143-54.8. Parks RJ, Chen L, Anton M, Sankar U, Rudnicki MA,Graham FL. A helper-dependent adenovirus vector system:removal of helper virus by Cre-mediated excisionof the viral packaging signal. Proc Natl Acad Sci USA1996; 93:13565-70.9. Schiedner G, Morral N, Parks RJ, Wu Y, Koopmans SC,Langston C, et al. Genomic DNA transfer with a highcapacityadenovirus vector results in improved in vivogene expression and decreased toxicity. Nat Genet 1998;18:180-3.10. Harvey BG, Hackett NR, El Sawy T, Rosengart TK,Hirschowitz EA, Lieberman MD, et al. Variability ofhuman systemic humoral immune responses to adenovirusgene transfer vectors administered to differentorgans. J Virol 1999; 73:6729-42.11. Crystal RG, Harvey BG, Wisnivesky JP, O'DonoghueKA, Chu KW, Maroni J, et al. Analysis of risk factors forlocal delivery of low- and intermediate- dose adenovirusgene transfer vectors to individuals with a spectrum ofcomorbid conditions. Hum Gene Ther 2002; 13:65-100.12. Connelly S, Andrews JL, Gallo AM, Kayda DB, Qian J,Hoyer L, et al. Sustained phenotypic correction ofmurine hemophilia A by in vivo gene therapy. Blood1998; 91:3273-81.13. Gallo-Penn AM, Shirley PS, Andrews JL, Kayda DB,Pinkstaff AM, Kaloss M, et al. In vivo evaluation of anadenoviral vector encoding canine factor VIII: high-level,sustained expression in hemophiliac mice. HumGene Ther 1999; 10:1791-802.14. Balague C, Zhou J, Dai Y, Alemany R, Josephs SF,Andreason G et al. Sustained high-level expression offull-length human factor VIII and restoration of clottingactivity in hemophilic mice using a minimal adenovirusvector. Blood 2000; 95:820-8.15. Nasto B. Questions about Systemic Adenovirus Delivery.Mol Ther 2002; 5:652-3.haematologica vol. 88(supplement n. 12):september 2003
[Gene Therapy]review paperGene therapy for hemophilia A:immune consequences of viralvectormediated factor VIIIgene transferhaematologica 2003; 88(suppl. n. 12):115-121http://www.haematologica.org/free/immunotolerance2001.pdfTHIERRY VANDENDRIESSCHE, DESIRE COLLEN,MARINEE K.L. CHUAHCenter for Transgene Technology and Gene Therapy,Flanders Interuniversity Institute for Biotechnology-Universityof Leuven, BelgiumObjective. Hemophilia A is potentially amenable fortreatment by gene therapy. We have been exploringthe use of different viral vectors including onco-retroviral,lentiviral and high-capacity adenoviral (HC-Ad),each with their own advantages and limitations, forhemophilia A gene therapy.Study design. Injection of onco-retroviral vectorsencoding the B-domain deleted human FVIII cDNAinto neonatal hemophilia A mice resulted in longtermexpression of therapeutic and even supra-physiologicFVIII levels that stably corrected the bleedingdiathesis in 50% of the recipient mice. The lack ofneutralizing antibodies specific for human FVIII inthese animals, may have been due to the inductionof neonatal tolerance. However, in the remainingrecipient mice, a humoral and possibly also a cellularimmune response developed which thwarted phenotypiccorrection. Since onco-retroviral transductionis restricted to rapidly dividing target cells, efficienthepatic gene transfer could only be achievedin neonates but not in adult mice. To overcome thislimitation, lentiviral vectors were employed instead.Results. Non-dividing hepatocytes in adult recipientmice can be efficiently transduced (5-10%) usingimproved lentiviral vector designs, leading to longtermtransgene expression with only limited and transienthepatotoxicity. This underscores the potentialof lentiviral vectors for hemophilia gene therapy.However, efficient gene transfer was also apparentin antigen-presenting cells (APCs), particularly inKupffer cells, splenic macrophages and B-lymphocytes.Since it has previously been shown that inadvertenttransgene expression in APC triggers thedevelopment of neutralizing antibodies, the use ofCorrespondence: Thierry VandenDriessche, MD, Center forTransgene Technology and Gene Therapy, Flanders InteruniversityInstitute for Biotechnology, University of Leuven, 49 HerestraatB-3000 Leuven, Belgium. Phone: international+32.16.346144. Fax: international +32.16.34599. E-mail:thierry.vandendriessche@med.kuleuven.ac.be ormarineekhim.chuah@med.kuleuven.ac.behepatocyte-specific promoters may be warranted tocircumvent this potential risk. Finally, we have shownthat high-capacity adenoviral vectors can be used toachieve unprecedented high levels of human FVIIIexpression in hemophilic mice but that humoral andpossibly also cellular immune responses precludedlong-term gene expression.Conclusions. In conclusion, the use of different replication-deficientviral vectors that do not encode viralantigens can be used to express therapeutic levelsof human FVIII in hemophilic mice with varying efficiencies.However, the development of neutralizingantibodies following gene therapy in conjunctionwith the induction of cellular immune responsesagainst the transduced target cells, remains a concernthat will need to be addressed further in largeanimal models, such as hemophilic dogs, withspecies-specific transgenes.©2003, Ferrata Storti FoundationKey words: hemophilia; factor VIII; coagulation; genetherapy; inhibitory antibodies.Though factor VIII (FVIII) substitution therapyhas greatly improved the lives of patientssuffering from hemophilia A, there are stilllimitations to the current treatment that havetriggered interest in alternative treatments bygene therapy. Significant progress has recentlybeen made in the development of gene therapyfor the treatment of hemophilia A that serves asan ideal trailblazer for the treatment of other diseasesby gene therapy. These advances parallelthe technical improvements of existing viral vectorsystems and the development of new deliverymethods. 1-3 Both viral vectors as well as non-viralvectors have been considered for the developmentof hemophilia gene therapy. In general,viral vector-mediated gene transfer is far moreefficient than non-viral gene transfer and hastherefore been the method of choice.What is the ideal gene therapy vector forhemophilia A? The ideal gene therapy vectorwould need to have the following properties:haematologica vol. 88(supplement n. 12):september 2003
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