Abstract
Science Wire
MicroRNA Regulates the ‘Good Cholesterol’
Two recent studies published in Science have independently shown that microRNA-33 (miR-33) is an important regulator of high density lipoprotein cholesterol (HDL-C) homeostasis (1,2). HDL particles transport excess cholesterol from peripheral cells to the liver for excretion into bile or to organs involved in steroid hormone synthesis; this process is called reverse cholesterol transport (RCT). Population studies have shown a highly consistent, inverse correlation between plasma concentrations of HDL-C and atherosclerotic cardiovascular disease risk in humans.
MicroRNAs are short RNA molecules that bind to complementary sequences in the 3′ untranslated regions of target mRNA transcripts and usually result in gene silencing. It is estimated that the human genome encodes over 1000 miRNAs which may target about 60% of mammalian genes. MiR-33 is encoded by a sequence embedded within introns of the sterol response element-binding factors (SREBFs), which are transcription factors that regulate the expression of genes involved in the biosynthesis and cellular uptake of cholesterol.
MiR-33 was identified by two different routes in these studies. Rayner and colleagues used a genome-wide screen of microRNAs that were differentially modulated by cellular cholesterol depletion and enrichment, whereas Najafi-Shoushtari and colleagues undertook studies of gene regulation by SREBFs. The authors found miR-33 to be present in various cells and tissues, including liver, macrophages, colon, small intestine, brain and skeletal muscle. The ATP binding cassette transporter (ABCA1), was found to be the primary target of miR-33. ABCA1 functions primarily in macrophages and hepatocytes. In macrophages, it excretes cholesterol that accumulates as a result of the uptake of oxidized cholesterol-carrying lipoproteins. In liver, ABCA1 is essential for the production of the precursor forms of HDL. The authors found that lentiviral-mediated overexpression of miR-33 leads to a reduction of ABCA1 protein levels and that hepatic miR-33 levels are inversely correlated with cholesterol levels and Abca1 gene expression.
The authors investigated the effects of reducing miR-33 levels in mice. Rayner et al. used lentiviral delivery of anti-miR-33, and showed that this led to a significant increase of plasma HDL levels in mice. Similar results were seen by Najafi-Shoushtari et al., who used miR-33-specific antisense RNA and demonstrated that antisense RNA-treated animals had no changes in the levels of low-density lipoprotein cholesterol, triglyceride or glucose. Collectively, these studies show a new role for miR-33 in the epigenetic regulation of cholesterol homeostasis and suggest miR-33 to be a novel target of cardiovascular disorders. It will be important for future studies to optimize the knockdown strategies and provide further proof-of-concept in animal models of disease. (sk)
References
Regulatory Wire
EMA Introduces New Website
The European Medicines Agency (EMA) revealed its newly redesigned corporate website at
Some of the website's new features include: ○ Quick medicine searches: Allows you to search for human and veterinary medicines by name and active substance and for herbal medicinal substances by name. ○ An online library: Enables you to search for all Agency documents currently online by title and date published online. ○ Improved navigation: More intuitive labeling and improved organization of content so that browsing is quicker for all audience groups. ○ Audience landing pages: Flags information of specific value to different key users. ○ Online calendar and news search: Allows you to keep up to date with the latest news and events at the Agency. ○ RSS feeds: Brings information straight to you as soon as it is published online.
The EMA will continue to work on improving the website through 2010 and 2011. (sk)
EMA Issues Reflection Paper on AAV
The EMA has published a new reflection paper on “Quality, Non-Clinical, and Clinical Issues Related to the Development of Recombinant Adeno Associated Viral Vectors.” The document discusses non-clinical and clinical issues that should be considered during the development of medicinal products derived from AAV, and highlights the requirements that might be expected at the time of a market authorization application (MAA). Among the topics discussed are: Manufacturing methodologies used to generate preclinical and clinical grade rAAV. Quality control evaluation of the product. Guidance on biodistribution and shedding studies. Immunogenicity considerations, including issues pertaining to the use of immunosuppressive agents.
A complete copy of the reflection paper can be found at the EMA's website:
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