construct administered by peripheral intravenous infusion Phase I trial of FVIII gene transfer for severe hemophilia A using a retroviral

Abstract In a phase I dose escalation study, 13 subjects with hemophilia A received by peripheral intravenous infusion a retroviral vector carrying a B-domain deleted human factor VIII gene. Infusions were well tolerated. Tests for replication competent retrovirus have been negative. PCR analyses demonstrate the persistence of vector gene sequences in peripheral blood mononuclear cells in 3 of 3 subjects tested. Factor VIII was measured in serial samples using both a one stage clotting assay and a chromogenic assay. While no subject had sustained FVIII increases, nine subjects had FVIII > 1% on at least two occasions five or more days after infusion of exogenous FVIII, with isolated levels that ranged from 2.3 to 19%. Pharmacokinetic parameters of exogenous FVIII infused into subjects 13 weeks after vector infusion showed an increased half-life (T1/2, p<0.02) and area under the curve (AUC, p<0.04) compared to pre-study values. Bleeding frequency decreased in 5 subjects compared to historical rates. These results demonstrate that this retroviral vector (hFVIII(V)) is safe and, in some subjects, persists up to a year in peripheral blood mononuclear cells, with measurable Factor VIII levels and with increased available FVIII activity (increased T1/2 and AUC) after infusion of exogenous FVIII concentrate.From bloodjournal.hematologylibrary.org by guest on May 31, 2013. For personal use only.

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