title: Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion.
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.
authors.affiliation: 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
authors.forename: Jerry S
authors.initials: JS
authors.lastname: Powell
authors.forename: Margaret V
authors.initials: MV
authors.lastname: Ragni
authors.forename: Gilbert C
authors.initials: GC
authors.lastname: White
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Lusher
authors.forename: Carol
authors.initials: C
authors.lastname: Hillman-Wiseman
authors.forename: Tom E
authors.initials: TE
authors.lastname: Moon
authors.forename: Veronica
authors.initials: V
authors.lastname: Cole
authors.forename: Sandhya
authors.initials: S
authors.lastname: Ramanathan-Girish
authors.forename: Holger
authors.initials: H
authors.lastname: Roehl
authors.forename: Nancy
authors.initials: N
authors.lastname: Sajjadi
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Jolly
authors.forename: Deborah
authors.initials: D
authors.lastname: Hurst
mesh_terms: D000293:Adolescent; D000328:Adult; D004279:DNA, Viral / Q000032:analysis; D005169:Factor VIII / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006467:Hemophilia A / Q000628:therapy*; D006801:Humans; D007262:Infusions, Intravenous; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008297:Male; D008875:Middle Aged; D012190:Retroviridae / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D004279:DNA, Viral; D005169:Factor VIII