| Title | Complete correction of hemophilia A with adeno-associated viral vectors containing a full-size expression cassette |
| Authors | Lu, Hui Chen, Lingxia Wang, Jinhui Huack, Bernd Sarkar, Rita Zhou, Shangzhen Xu, Ray Ding, Qiulan Wang, Xuefeng Wang, Hongli Xiao, Weidong |
| Affiliation | Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Univ Penn, Med Ctr, Dept Pediat, Philadelphia, PA 19104 USA. Peking Univ, Peoples Hosp, Beijing 100044, Peoples R China. Huaqiao Univ, Inst Mol Med, Quanzhou 362021, Fujian Province, Peoples R China. Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Shanghai 200025, Peoples R China. Childrens Hosp Philadelphia, 302B Abramson Res Ctr,3615 Civic Ctr Blvd, Philadelphia, PA 19104 USA. |
| Keywords | PACKAGING CAPACITY GENE-THERAPY FACTOR-VIII VIRUS SECRETION HEAVY FVIII MICE |
| Issue Date | 2008 |
| Publisher | human gene therapy |
| Citation | HUMAN GENE THERAPY.2008,19,(6),648-654. |
| Abstract | Hemophilia A is caused by a deficiency in the factor VIII (FVIII) gene. Constrained by limited packaging capacity, even the 4.3-kb B domain-deleted FVIII remained a challenge for delivery by a single adeno-associated viral (AAV) vector. Studies have shown that up to a 6.6-kb vector sequence may be packaged into AAV virions, which suggested an alternative strategy for hemophilia A gene therapy. To explore the usefulness of AAV vectors carrying an oversized FVIII gene, we constructed the AAV-FVIII vector under the control of a P-actin promoter with a cytomegalovirus enhancer (CB) and a bovine growth hormone (bGH) poly(A) sequence. The CB promoter plus bGH signal was shown to be 3- to 5-fold more potent than the mini-transthyretin (TTR) promoter with a synthetic poly(A) sequence for directing FVIII expression in the liver. Despite the 5.75-kb genome size of pAAV-CB-FVIII, sufficient AAV vectors were produced for in vivo testing. Approximately 3- to 5-fold more FVIII secretion was observed in animals receiving AAV-CB-FVIII vectors than in those receiving Standard-sized AAV-TTR-FVIII vectors. Both the activated partial thromboplastin time assay and the whole blood thromboelastographic analysis confirmed that AAV-FVIII vectors fully corrected the bleeding phenotype of hemophilia mice. These results suggest that AAV vectors with an oversized genome should be useful for not only hemophilia A gene therapy but also other diseases with large cDNA such as muscular dystrophy and cystic fibrosis. |
| URI | http://hdl.handle.net/20.500.11897/397343 |
| ISSN | 1043-0342 |
| DOI | 10.1089/hum.2007.0182 |
| Indexed | SCI(E) |
| Appears in Collections: | 人民医院 |
