Development and analysis of retroviral vectors expressing human factor VIII as a potential gene therapy for hemophilia A.

Abstract:

:To develop a potential gene therapy strategy for the treatment of hemophilia A, we constructed several retroviral vectors expressing a B-domain-deleted factor VIII (FVIII) cDNA. We confirmed previous reports that when the FVIII cDNA is inserted into a retroviral vector, the vector mRNA is decreased resulting in significantly (100- to 1,000-fold) lower vector titers. In an attempt to overcome this inhibition we pursued two independent strategies. First, site-directed mutagenesis was employed to change the structure of a putative 1.2-kb FVIII RNA inhibitory sequence (INS). Second, the FVIII gene was transcribed from a retroviral vector containing a 5' intron. Results demonstrated that the intron increased FVIII expression up to 20-fold and viral titer up to 40-fold but conservative mutagenesis of the putative FVIII INS region failed to yield a significant increase in FVIII expression or titer. Using the improved FVIII splicing vector, we transduced a variety of cell types and were able to demonstrate relatively high FVIII expression (10-60 ng of FVIII/10(6) cells/24 hr). These results underscore the usefulness of these transduced cell types for potential in vivo delivery of FVIII.

journal_name

Hum Gene Ther

journal_title

Human gene therapy

authors

Chuah MK,VandenDriessche T,Morgan RA

doi

10.1089/hum.1995.6.11-1363

subject

Has Abstract

pub_date

1995-11-01 00:00:00

pages

1363-77

issue

11

eissn

1043-0342

issn

1557-7422

journal_volume

6

pub_type

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