Abstract:
:Gene therapy for hemophilia A requires efficient delivery of the factor VIII gene and sustained protein expression at circulating levels of at least 1% to 2% of normal. Adeno-associated viral type 2 (AAV2) vectors have a number of advantages over other viral vectors, including an excellent safety profile and persistent gene expression. However, a major disadvantage is their small packaging capacity, which has hampered their use in treating diseases such as hemophilia A, cystic fibrosis, and muscular dystrophy, which are caused by mutations in large genes. Here we demonstrate that this can be overcome by using small regulatory elements to drive expression of a B-domain-deleted form of FVIII. The use of this vector for hepatic gene transfer in a canine model of hemophilia A resulted in the sustained (> 14 months) expression of biologically active FVIII. FVIII activity levels of 2% to 4% were achieved. These levels correlated with a partial correction in the whole-blood clotting time and cuticle bleeding time. In addition, immunoprecipitation analysis demonstrated the expression of canine FVIII of the predicted size in the plasma of injected animals. These data support the use of AAV2 vectors in human clinical trials to treat hemophilia A patients.
journal_name
Bloodjournal_title
Bloodauthors
Scallan CD,Lillicrap D,Jiang H,Qian X,Patarroyo-White SL,Parker AE,Liu T,Vargas J,Nagy D,Powell SK,Wright JF,Turner PV,Tinlin SJ,Webster SE,McClelland A,Couto LBdoi
10.1182/blood-2003-01-0292subject
Has Abstractpub_date
2003-09-15 00:00:00pages
2031-7issue
6eissn
0006-4971issn
1528-0020pii
2003-01-0292journal_volume
102pub_type
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