Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant

被引:221
作者
McIntosh, Jenny [1 ,2 ]
Lenting, Peter J. [3 ,4 ]
Rosales, Cecilia [1 ,2 ]
Lee, Doyoung [1 ]
Rabbanian, Samira [1 ,2 ]
Raj, Deepak [1 ,2 ]
Patel, Nishil [1 ]
Tuddenham, Edward G. D. [1 ,5 ,6 ]
Christophe, Olivier D. [3 ,4 ]
McVey, John H. [7 ]
Waddington, Simon [8 ]
Nienhuis, Arthur W. [9 ]
Gray, John T. [9 ]
Fagone, Paolo [9 ]
Mingozzi, Federico [10 ]
Zhou, Shang-Zhen [10 ]
High, Katherine A. [10 ,11 ]
Cancio, Maria [12 ]
Ng, Catherine Y. C. [12 ]
Zhou, Junfang [12 ]
Morton, Christopher L. [12 ]
Davidoff, Andrew M. [12 ]
Nathwani, Amit C. [1 ,2 ,5 ,6 ]
机构
[1] UCL, Inst Canc, London WC1E 6BT, England
[2] Natl Hlth Serv Blood & Transplant, Watford, Herts, England
[3] Univ Paris 11, INSERM, U770, Le Kremlin Bicetre, France
[4] Univ Paris 11, UMR, Le Kremlin Bicetre, France
[5] Royal Free Hosp, Katharine Dormandy Haemophilia Ctr, London NW3 2QG, England
[6] Royal Free Hosp, Thrombosis Unit, London NW3 2QG, England
[7] Kings Coll London, MRC, Ctr Transplantat, London WC2R 2LS, England
[8] UCL, Prenatal Cell & Gene Therapy Grp, London WC1E 6BT, England
[9] St Jude Childrens Res Hosp, Div Expt Hematol, Memphis, TN 38105 USA
[10] Childrens Hosp Philadelphia, Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA
[11] Childrens Hosp Philadelphia, Howard Hughes Med Inst, Philadelphia, PA 19104 USA
[12] St Jude Childrens Res Hosp, Dept Surg, Memphis, TN 38105 USA
基金
英国医学研究理事会;
关键词
ADENOASSOCIATED VIRAL VECTORS; RECOMBINANT FACTOR-VIII; MEDIATED GENE-TRANSFER; SEVERE HEMOPHILIA-A; COAGULATION-FACTOR VIII; FACTOR-IX EXPRESSION; EFFICIENT TRANSDUCTION; MONOCLONAL-ANTIBODIES; CAPSID PROTEINS; HEAVY-CHAIN;
D O I
10.1182/blood-2012-10-462200
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Recombinant adeno-associated virus (rAAV) vectors encoding human factor VIII (hFVIII) were systematically evaluated for hemophilia A (HA) gene therapy. A 5.7-kb rAAV-expression cassette (rAAV-HLP-codop-hFVIII-N6) containing a codon-optimized hFVIII cDNA in which a 226 amino acid (aa) B-domain spacer replaced the entire B domain and a hybrid liver-specific promoter (HLP) mediated 10-fold higher hFVIII levels in mice compared with non-codon-optimized variants. A further twofold improvement in potency was achieved by replacing the 226-aa N6 spacer with a novel 17-aa peptide (V3) in which 6 glycosylation triplets from the B domain were juxtaposed. The resulting 5.2-kb rAAV-HLP-codop-hFVIII-V3 cassette was more efficiently packaged within AAV virions and mediated supraphysiologic hFVIII expression (732 +/- 162% of normal) in HA knockout mice following administration of 2 x 10(12) vector genomes/kg, a vector dose shown to be safe in subjects with hemophilia B. Stable hFVIII expression at 15 +/- 4% of normal was observed at this dose in a nonhuman primate. hFVIII expression above 100% was observed in 3 macaques that received a higher dose of either this vector or the N6 variant. These animals developed neutralizing anti-FVIII antibodies that were abrogated with transient immunosuppression. Therefore, rAAV-HLP-codop-hFVIII-V3 substantially improves the prospects of effective HA gene therapy.
引用
收藏
页码:3335 / 3344
页数:10
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