期刊
MOLECULAR THERAPY
卷 16, 期 6, 页码 1089-1097出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mt.2008.56
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资金
- NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH [ZIADE000695] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCH [Z01DE000336] Funding Source: NIH RePORTER
- Intramural NIH HHS [Z01 DE000336-27] Funding Source: Medline
We studied the effects of specific retroviral elements in a first-generation serotype 5 adenoviral ( Ad5) vector, AdLTR(2)EF1 alpha-hEPO. This vector contains 858 base pair ( bp) [251-bp envelope sequence plus 607-bp long-terminal repeat ( LTR)] from Moloney murine leukemia virus ( MoMLV), upstream of the human elongation factor-1 alpha ( EF1 alpha) promoter and human erythropoietin ( hEPO) cDNA, with the LTR sequence downstream of the polyadenylation signal. We compared expression of AdLTR(2)EF1 alpha-hEPO with corresponding expressions of two conventional Ad5 vectors, AdEF1 alpha-hEPO and AdCMV-hEPO, in vivo in submandibular glands in rats. Both the conventional vectors yielded low serum hEPO levels by day 7, and little change in hematocrits. In contrast, after receiving AdLTR(2)EF1 alpha-hEPO, the rats showed elevated hEPO levels and hematocrits for 1-3 months. In vitro studies showed that the integration efficiencies of all the vectors were similar (similar to 10(-3)). Approximately 0.1% of the vector genomes were present 1 year after delivery in the case of each of the three vectors, primarily as intact linear double-strand DNA. The unique results seen with AdLTR(2)EF1 alpha-hEPO are partly because of LTR enhancer activity. However, other cis-acting activity, which is not immunomodulatory but nevertheless influences promoter methylation, appears to be involved. A vector such as AdLTR(2)EF1 alpha-hEPO may prove useful in clinical applications in which extended, but not permanent, transgene expression is desirable.
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