Abstract
“Epigenetherapy” alters epigenetic status of the targeted chromatin and modifies expression of the endogenous therapeutic gene. In this study we used lentiviral in vivo delivery of small hairpin RNA (shRNA) into hearts in a murine infarction model. shRNA complementary to the promoter of vascular endothelial growth factor (VEGF-A) was able to upregulate endogenous VEGF-A expression. Histological and multiphoton microscope analysis confirmed the therapeutic effect in the transduced hearts. Magnetic resonance imaging (MRI) showed in vivo that the infarct size was significantly reduced in the treatment group 14 days after the epigenetherapy. Importantly, we show that promoter-targeted shRNA upregulates all isoforms of endogenous VEGF-A and that an intact hairpin structure is required for the shRNA activity. In conclusion, regulation of gene expression at the promoter level is a promising new treatment strategy for myocardial infarction and also potentially useful for the upregulation of other endogenous genes.
Highlights
The prevalence of chronic ischemic heart disease is steadily increasing due to increased life expectancy
We delivered a lentiviral vector (LV) expressing small hairpin RNA (shRNA) that is targeted to the promoter area of the murine VEGF-A and upregulates its expression by an epigenetic mechanism (LV-451)
In this study we analyzed the therapeutic potential of Epigenetherapy and epigenetic upregulation of endogenous VEGF-A in infarcted murine hearts and found a significant reduction in infarct size two weeks post treatment
Summary
The prevalence of chronic ischemic heart disease is steadily increasing due to increased life expectancy. Narrowing of coronary arteries by atherosclerotic plaques or acute occlusion by thrombosis can lead to myocardial infarction (MI) and heart failure. Bypass surgery and stenting are the first choices of therapy for severe coronary heart disease patients. Surgical treatments are not suitable for all patients and long-term outcome, due to e.g. in-stent restenosis, is still sometimes poor. Gene therapy strategies aim at ectopic expression of a transgene delivered by viral or non-viral vectors. Small RNAs have been delivered for inhibition of target genes by RNA interference (RNAi). Major problems in clinical gene therapy have been inefficient delivery of transgenes and immune responses, leading to limited efficiency of the treatments [1]
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