Article
Refine
Document Type
- Article (2) (remove)
Language
- English (2)
Has Fulltext
- yes (2)
Is part of the Bibliography
- no (2)
Keywords
- siRNA (2) (remove)
Institute
- Medizin (2) (remove)
Since our knowledge on structure and function of messenger RNA (mRNA) has expanded from merely being an intermediate molecule between DNA and proteins to the notion that RNA is a dynamic gene regulator that can be modified and edited, RNA has become a focus of interest into developing novel therapeutic schemes. Therapeutic modulation of RNA molecules by DNA- and RNA-based therapies has broadened the scope of therapeutic targets in infectious diseases, cancer, neurodegenerative diseases and most recently in cardiovascular diseases as well. Currently, antisense oligonucleotides (ASO), small interfering RNAs (siRNAs), and microRNAs are the most widely applied therapeutic strategies to target RNA molecules and regulate gene expression and protein production. However, a number of barriers have to be overcome including instability, inadequate binding affinity and delivery to the tissues, immunogenicity, and off-target toxicity in order for these agents to evolve into efficient drugs. As cardiovascular diseases remain the leading cause of mortality worldwide, a large number of clinical trials are under development investigating the safety and efficacy of RNA therapeutics in clinical conditions such as familial hypercholesterolemia, diabetes mellitus, hypertriglyceridemia, cardiac amyloidosis, and atrial fibrillation. In this review, we summarize the clinical trials of RNA-targeting therapies in cardiovascular disease and critically discuss the advances, the outcomes, the limitations and the future directions of RNA therapeutics in precision transcriptomic medicine.
In eukaryotes, double-stranded (ds) RNA induces sequence-specific inhibition of gene expression referred to as RNA interference (RNAi). We exploited RNAi to define the role of HER2/neu in the neoplastic proliferation of human breast cancer cells. We transfected SK-BR-3, BT-474, MCF-7, and MDA-MB-468 breast cancer cells with short interfering RNA (siRNA) targeted against human HER2/neu and analyzed the specific inhibition of HER2/neu expression by Northern and Western blots. Transfection with HER2/neu-specific siRNA resulted in a sequence-specific decrease in HER2/neu mRNA and protein levels. Moreover, transfection with HER2/neu siRNA caused cell cycle arrest at G0/G1 in the breast cancer cell lines SKBR-3 and BT-474, consistent with a powerful RNA silencing effect. siRNA treatment resulted in an antiproliferative and apoptotic response in cells overexpressing HER2/neu, but had no influence in cells with almost no expression of HER2/neu proteins like MDA-MB-468 cells. These data indicate that HER2/neu function is essential for the proliferation of HER2/neuoverexpressing breast cancer cells. Our observations suggest that siRNA targeted against human HER2/neu may be valuable tools as anti proliferative agents that display activity against neoplastic cells at very low doses.