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KMID : 0379519990150030373
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한국독성학회지
1999 Volume.15 No. 3 p.373 ~ p.378
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Safety Test of Plasmid Expressing VEGF for Peripheral Artery Occlusive Disease in Animal Model
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Lee Young-Joo
Park Eun-Jin
Cho Hong-Chan
Suh Yeon-Lim
Kim Duk-Kyung
Kim Sun-Young
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Abstract
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It has been demonstrated that injection of naked DNA expressing vascular endothelial growth factor (VEGF) to the affected area can provide significant therapeutic effects on peripheral artery occlusive disease. Success with this type of gene therapy highly depends on the quality of the vector delivering the therapeutic gene, especially in terms of the level and duration of gene expression in the localized area. We have recently developed an expression vector that can produce significantly higher levels of VEGF in the mouse model. This report is part of preclinical studies documenting the safety of this newly developed expression plasmids expressing VEGF165 (pCN-VEGF and pCK-VEGF) in the BALB/C mouse model. When these naked DNAs were introduced to the anterior tibialis muscle of the mouse, VEGF was transiently expressed at the site of injection. To test the possibility of movement of the injected plasmid to other tissues, which might potentially cause undesirable side effects, we have examined plasmid dissemination by polymerase chain reaction (PCR) of DNAs isolated from various tissues (heart, liver, lung, spleen, testis, muscle) at 2 days following the injection of naked DNA. Despite high level expression of the VEGF protein in anterior tibialis muscle treated with naked DNA, the exogenously added gene was not detectable in tissues other than the injected area. This is probably due to the instability of naked DNA in the blood stream as well as the extreme inefficiency of naked DNA in reaching the nucleus and driving gene expression in cell types other than muscle. We have systematically retrieved various tissue sections (liver, heart, testis, lung, spleen, muscle) and examined for pathological features that could be caused by the presence of naked DNA and expression of VEGF. No pathological features were found in all tissues and organs tested. Specifically, no evidence of neoangiogenisis was identified in any tissue specimens. Similarly, no histological evidence of a pathologic immune response was observed.
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KEYWORD
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Ischemic disease, Naked DNA gene therapy, VEGF
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