Faculty Collaboration Database

Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion. Blood 2003 Sep 15;102(6):2038-45

Date

05/24/2003

Pubmed ID

12763932

DOI

10.1182/blood-2003-01-0167

Scopus ID

2-s2.0-0141679053 (requires institutional sign-in at Scopus site)   178 Citations

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.

Author List

Powell JS, Ragni MV, White GC 2nd, Lusher JM, Hillman-Wiseman C, Moon TE, Cole V, Ramanathan-Girish S, Roehl H, Sajjadi N, Jolly DJ, Hurst D

Author

Gilbert C. White MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
DNA, Viral
Factor VIII
Genetic Therapy
Genetic Vectors
Hemophilia A
Humans
Infusions, Intravenous
Leukocytes, Mononuclear
Male
Middle Aged
Retroviridae
Severity of Illness Index