Gene transfer as an approach to treating hemophilia

被引:40
作者
High, KA [1 ]
机构
[1] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Abramson Res Ctr 310,Hematol Div, Philadelphia, PA 19104 USA
关键词
gene therapy; adenovirus; retrovirus; AAV; hemophilia A; hemophilia B;
D O I
10.1055/s-2003-37945
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Gene therapy is a novel area of therapeutics in which the active agent is a nucleic acid sequence rather than a protein or small molecule. Successful clinical applications of gene transfer have been limited to date because of shortcomings in the available gene delivery vehicles. The goal of gene transfer for hemophilia is to achieve sustained expression of factor (F) VIII or FIX at levels high enough to improve the symptoms of the disease. Hemophilia has proved to be an attractive model for those interested in gene transfer, and multiple gene transfer strategies are currently being investigated. So far, five different trials, three for hemophilia A and two for hemophilia B, have enrolled approximately 40 patients with severe hemophilia. This article summarizes the gene transfer strategies being investigated, the available preclinical data, and the early clinical results. In the past year, several groups have demonstrated sustained expression of clotting factors at levels of 5 to 10% of normal in large animal models of hemophilia. The goal of the ongoing clinical studies is to determine whether these results can safely be extended to humans.
引用
收藏
页码:107 / 119
页数:13
相关论文
共 103 条
[71]   Factors influencing in vivo transduction by recombinant adeno-associated viral vectors expressing the human factor IX cDNA [J].
Nathwani, AC ;
Davidoff, A ;
Hanawa, H ;
Zhou, JF ;
Vanin, EF ;
Nienhuis, AW .
BLOOD, 2001, 97 (05) :1258-1265
[72]  
*NIH OFF BIOT, 2002, PHAS I SAF STUD PAT
[73]  
*NIH OFF BIOT ACT, 2002, PHAS 1 SINGL DOS DOS
[74]  
Oka K, 2001, CIRCULATION, V103, P1274
[75]   A helper-dependent adenovirus vector system: Removal of helper virus by Cre-mediated excision of the viral packaging signal [J].
Parks, RJ ;
Chen, L ;
Anton, M ;
Sankar, U ;
Rudnicki, MA ;
Graham, FL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (24) :13565-13570
[76]   Use of a liver-specific promoter reduces immune response to the transgene in adenoviral vectors [J].
Pastore, L ;
Morral, N ;
Zhou, HS ;
Garcia, R ;
Parks, RJ ;
Kochanek, S ;
Graham, FL ;
Lee, B ;
Beaudet, AL .
HUMAN GENE THERAPY, 1999, 10 (11) :1773-1781
[77]  
Powell JS, 2001, BLOOD, V98, p693A
[78]   Analysis of testes and semen from rabbits treated by intravenous injection with a retroviral vector encoding the human factor VIII gene: No evidence of germ line transduction [J].
Roehl, HH ;
Leibbrandt, MEI ;
Greengard, JS ;
Kamantigue, E ;
Glass, WG ;
Giedlin, M ;
Boekelheide, K ;
Johnson, DE ;
Jolly, DJ ;
Sajjadi, NC .
HUMAN GENE THERAPY, 2000, 11 (18) :2529-2540
[79]   Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A [J].
Roth, DA ;
Tawa, NE ;
O'Brien, JM ;
Treco, DA ;
Selden, RF .
NEW ENGLAND JOURNAL OF MEDICINE, 2001, 344 (23) :1735-1742
[80]   Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity [J].
Schiedner, G ;
Morral, N ;
Parks, RJ ;
Wu, Y ;
Koopmans, SC ;
Langston, C ;
Graham, FL ;
Beaudet, AL ;
Kochanek, S .
NATURE GENETICS, 1998, 18 (02) :180-183