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Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion.
Powell, Jerry S; Ragni, Margaret V; White, Gilbert C; Lusher, Jeanne M; Hillman-Wiseman, Carol; Moon, Tom E; Cole, Veronica; Ramanathan-Girish, Sandhya; Roehl, Holger; Sajjadi, Nancy; Jolly, Douglas J; Hurst, Deborah.
Afiliación
  • Powell JS; Division of Hematology and Oncology, Suite 3016, UC-Davis Cancer Center, University of California at Davis, 4501 X St, Sacramento, CA 95817. jspowell@ucdavis.edu
Blood ; 102(6): 2038-45, 2003 Sep 15.
Article en En | MEDLINE | ID: mdl-12763932
ABSTRACT
In a phase 1 dose escalation study, 13 subjects with hemophilia A received by peripheral intravenous infusion a retroviral vector carrying a B-domain-deleted human factor VIII (hFVIII) gene. Infusions were well tolerated. Tests for replication competent retrovirus have been negative. Polymerase chain reaction (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, 9 subjects had FVIII higher than 1% on at least 2 occasions 5 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 <.02) and area under the curve (AUC, P <.04) compared with prestudy values. Bleeding frequency decreased in 5 subjects compared with historical rates. These results demonstrate that this retroviral vector (hFVIII(V)) is safe and, in some subjects, persists more than 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.
Asunto(s)
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Retroviridae / Factor VIII / Terapia Genética / Vectores Genéticos / Hemofilia A Tipo de estudio: Clinical_trials / Prognostic_studies Límite: Adolescent / Adult / Humans / Male / Middle aged Idioma: En Revista: Blood Año: 2003 Tipo del documento: Article
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Retroviridae / Factor VIII / Terapia Genética / Vectores Genéticos / Hemofilia A Tipo de estudio: Clinical_trials / Prognostic_studies Límite: Adolescent / Adult / Humans / Male / Middle aged Idioma: En Revista: Blood Año: 2003 Tipo del documento: Article