Back to Search
Start Over
Long-term Transgene Expression from Plasmid DNA Gene Therapy Vectors Is Negatively Affected by CpG Dinucleotides
- Source :
-
Molecular Therapy . Aug2004, Vol. 10 Issue 2, p269-278. 10p. - Publication Year :
- 2004
-
Abstract
- CpG-reduced, CMV-based plasmid DNA constructs encoding human α-galactosidase A and factor IX were injected into C57Bl/6, BALB/c, and CD1 mice using hydrodynamics-based delivery of plasmid DNA (pDNA), and gene expression was monitored for 6 months. Linearized and supercoiled pDNAs were compared for their abilities to support long-term expression and to generate immune responses to the transgene product. In all mouse strains supercoiled CpG-reduced pDNA encoding α-galactosidase A and factor IX generated higher and more sustained levels of circulating gene product than their supercoiled CpG-replete analogs. Linearizing supercoiled CpG-reduced pDNA did not significantly increase levels of circulating gene product beyond levels supercoiled CpG-reduced pDNA could achieve. Linearizing supercoiled CpG-replete pDNA vectors significantly increased expression compared to their supercoiled CpG-replete analogs, but the increase was short-lived or subtherapeutic. Regardless of vector, liver depot expression did not elicit significant antibody responses to human α-galactosidase A or factor IX. Taken together, these data suggest that a clinically acceptable hydrodynamics-based approach targeting the liver combined with CpG-reduced pDNA vectors may represent a viable option for individuals with hemophilia, a lysosomal storage disease, or other disease in which prolonged depot expression of a therapeutic protein from the liver is desirable. [Copyright &y& Elsevier]
- Subjects :
- *GENE therapy
*GENETIC engineering
*HEMOPHILIA
*BLOOD diseases
Subjects
Details
- Language :
- English
- ISSN :
- 15250016
- Volume :
- 10
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Molecular Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 13958611
- Full Text :
- https://doi.org/10.1016/j.ymthe.2004.04.018