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- Title
Long-term Transgene Expression from Plasmid DNA Gene Therapy Vectors Is Negatively Affected by CpG Dinucleotides
- Authors
Hodges, Bradley L.; Taylor, Kristin M.; Joseph, Macy F.; Bourgeois, Sarah A.; Scheule, Ronald K.
- 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.
- Subjects
GENE therapy; GENETIC engineering; HEMOPHILIA; BLOOD diseases
- Publication
Molecular Therapy, 2004, Vol 10, Issue 2, p269
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1016/j.ymthe.2004.04.018