TY - JOUR
T1 - Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion
AU - Powell, Jerry S
AU - Ragni, Margaret V.
AU - White, Gilbert C.
AU - Lusher, Jeanne M.
AU - Hillman-Wiseman, Carol
AU - Moon, Tom E.
AU - Cole, Veronica
AU - Ramanathan-Girish, Sandhya
AU - Roehl, Holger
AU - Sajjadi, Nancy
AU - Jolly, Douglas J.
AU - Hurst, Deborah
PY - 2003/9/15
Y1 - 2003/9/15
N2 - 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 pre-study 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.
AB - 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 pre-study 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.
UR - http://www.scopus.com/inward/record.url?scp=0141679053&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0141679053&partnerID=8YFLogxK
U2 - 10.1182/blood-2003-01-0167
DO - 10.1182/blood-2003-01-0167
M3 - Article
C2 - 12763932
AN - SCOPUS:0141679053
VL - 102
SP - 2038
EP - 2045
JO - Blood
JF - Blood
SN - 0006-4971
IS - 6
ER -