miRNA Blog

Mayo Clinic Health Letter Highlights – July

Chris — Thu, 22 Jul 2010 22:31:58 +0000

MicroRNA — A Switch that Determines Cell Behavior and Holds Answers on Disease, Prevention, Treatment

ROCHESTER, Minn. — Thousands of research studies are under way to better understand microRNA — short for micro ribonucleic acid. These tiny genetic strands may play a role in identifying, treating and possibly preventing many diseases, according to the July issue of Mayo Clinic Health Letter.

MicroRNA acts like a switch that changes cell behavior. Different microRNAs are in each tissue of the body. For instance, what makes liver cells unique is, in part, their expression of a particular microRNA that influences which protein is produced.

About 1,000 distinct human microRNAs have been identified. Each can influence and regulate expression of hundreds of genes that determine a major change for the cell, such as whether it lives or dies, multiplies rapidly or develops into bone, muscle or another type of cell.

MicroRNA is a relatively new discovery. Scientists have been aware of its role for about 20 years, and there is still much to be learned. Scientists hope that microRNA research might eventually lead to improved diagnosis, more accurate predictions of disease outcomes and new treatment and medication options with fewer side effects.

Diseases being studied include:

Heart failure — MicroRNAs associated with this disease process may eventually tie into innovative therapeutic approaches.
Alzheimer’s disease — Studies have linked survival of brain cells (neurons) to their ability to produce microRNAs. Neurons incapable of doing so slowly die.
Hepatitis C virus — This virus “hijacks” certain microRNA to make copies of the virus within liver cells. Work is under way to develop a treatment that might keep the microRNA away from the virus.
Schizophrenia — Researchers are looking at possible associations between microRNA and this severe psychiatric disorder.
Cancer — Scientists have used microRNA to destroy liver cancer cells without harming healthy liver cells. Researchers have discovered a correlation between certain microRNAs and aggressive prostate cancer.

(See all the highlights… )

Pseudogenes act as “decoys” for microRNAs

Chris — Thu, 22 Jul 2010 15:26:50 +0000

MicroRNAs are known to regulate gene expression by interacting with incompletely complementary sequences in a target messenger RNA. But is the converse true: can mRNA expression affect the distribution of miRNAs? A new study¹shows that the 3′ untranslated region of a pseudogene — the tumour suppressor pseudogene PTENP1 — can bind the same miRNAs as the related protein-coding gene, PTEN. This suggests that pseudogenes may have a biological function as ‘decoys’, sequestering miRNAs and thereby affecting their regulation of expressed genes.

The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. However, given that microRNAs bind to RNAs, we hypothesized that RNAs could possess a regulatory role that relies on their ability to compete for microRNA binding, independently of their protein-coding function. As a model for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene PTENP1 and the critical consequences of this interaction. We find that PTENP1 is biologically active as it can regulate cellular levels of PTEN and exert a growth-suppressive role. We also show that the PTENP1 locus is selectively lost in human cancer. We extended our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. We also demonstrate that the transcripts of protein-coding genes such as PTEN are biologically active. These findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs. (Read more… )

Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi, PP. (2010) A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465, 1033-38. [abstract]

microRNAs and Transplantation

Chris — Wed, 21 Jul 2010 22:15:34 +0000

from The Online Transplant Center by Kenar D Jhaveri

A novel concept has been emerging in the last few years regarding micro RNAs. It already has reached some human data in transplant patients.
What is micro RNA? These are non coding areas of the RNA that play a critical role in regulation of gene expression. They might alter the structure and lead to either expression or regression of the protein in question.
There is mice data that microRNAs play a role in immune response, adaptive immunity, inflammation, fibrosis and epithelial changes. The role of microRNA will help us understand intracellular signalling, expression of proteins, modulation of cytokines, and graft response better.
Few simple examples are: miR 155 regulates immune response to bacterial infections and viral infections and helps in the crosstalk macrophage becoming an activated macrophage. Myeloid stem cell goes to becoming a mast cell due to miR 223; and so forth.
What is more fascinating is the role of this in Transplantation. How can this be useful in transplantation? they can be measured in serum, urine and plasma. Two studies have now shown that the micro RNA pattern in the in renal allograft biopsies is different in acute rejection episodes vs controls.
The future looks good:- These might be good panel of markers for allograft status. Therapeutic use of this application in altering the microRNA enviornment might be of advantage to prevent fibrosis or rejection. (read more… )

Grant Money Supporting microRNA Research

Chris — Fri, 09 Jul 2010 13:09:50 +0000

NIH Awards Three Grants Supporting RNAi, microRNA Rx Development -July 08, 2010

NIH Awards More Than $800K in March to Fund Three miRNA-Related Research Projects – March 11, 2010

NIH Awards Over $1M in FY ’10 Funding to miRNA-Related Research Projects – January 7, 2010

Rockefeller, OSU miRNA Researchers Pull in Big Bucks Under Recovery Act – October 22, 2009

NIH Awards Nearly $6M in RNAi, miRNA Grants with Stimulus Money – September 3, 2009

microRNA may Control Cocaine Addiction

Chris — Thu, 08 Jul 2010 14:35:01 +0000

NIH-Supported Finding on Cocaine Addiction: Tiny Molecule, Big Promise

NIDA News Release July 7, 2010

Discovery could lead to better ways of predicting drug abuse risk and treating addictions

A specific and remarkably small fragment of RNA appears to protect rats against cocaine addiction – and may also protect humans, according to a recent study funded by the National Institute on Drug Abuse (NIDA), a component of the National Institutes of Health. The study was published today in the journal Nature.

RNA (ribonucleic acid) molecules are known to play critical roles in the translation of genetic information (DNA) into proteins, which are the building blocks of life. In the past decade, scientists have begun to notice, catalogue and characterize a population of small RNAs, called microRNAs, that represent a new class of regulatory molecules. In this study, researchers at The Scripps Research Institute in Jupiter, Florida found that cocaine consumption increased levels of a specific microRNA sequence in the brains of rats, named microRNA-212. As its levels increased, the rats exhibited a growing dislike for cocaine, ultimately controlling how much they consumed. By contrast, as levels of microRNA-212 decreased, the rats consumed more cocaine and became the rat equivalent of compulsive users.

The study’s findings suggest that microRNA-212 plays a pivotal role in regulating cocaine intake in rats and perhaps in vulnerability to addiction. Interestingly, the same microRNA-212 identified in this study, is also expressed in the human’s dorsal striatum, a brain region that has been linked to drug abuse and habit formation.

“This study enhances our understanding of how brain mechanisms, at their most fundamental levels, may contribute to cocaine addiction vulnerability or resistance to it,” said NIDA Director Dr. Nora D. Volkow. “This research provides a wonderful example of how basic science discoveries are critical to the development of new medical treatments and targeted prevention.”

Rats with a history of extended cocaine access can demonstrate behavior similar to that observed in humans who are dependent on the drug. Current data show that about 15 percent of people who use cocaine become addicted to it. This study’s findings suggest that microRNAs may be important factors contributing to this vulnerability. (read more… )

microRNAs Play a role in Nicotine Addiction

Targeting a Master Regulator of Disease

Chris — Wed, 07 Jul 2010 14:39:56 +0000

Drugmakers place big bets on the emerging science of microRNA.

By Arlene Weintraub

San Diego startup Regulus, founded in 2007, has quietly been working on a new way to target RNA for drug development. The company has been studying a subset of RNA molecules called microRNAs, or miRNAs. First discovered in the 1990s, misbehaving miRNAs have been linked to several diseases, including cancer and heart failure. Drug developers hope these molecules will prove to be particularly effective drug targets because manipulating just one seems to suppress several disease-linked proteins–whereas most biotech drugs only target individual proteins.

Regulus is co-owned by Alnylam and Isis, leaders in RNA-based drug development. While it is just one of a handful of startups developing miRNA therapeutics, it has attracted significant attention from big pharmaceutical companies. Last month, French pharmaceutical giant Sanofi-Aventis announced a research alliance with the company. Sanofi has pledged up to $750 million in payments, including $35 million up front to Regulus–an unusually large investment in such early-stage science. Sanofi and Regulus will work together to target fibrosis, an excessive buildup of hard collagen that can wreak havoc on the heart, kidneys, and other organs. Regulus already has a multimillion-dollar alliance with GlaxoSmithKline to codevelop drugs to treat immune diseases and a hepatitis C treatment. (read more… )

microRNA of the Month – microRNA 219

Chris — Fri, 02 Jul 2010 13:23:39 +0000

microRNA-219 is highly expressed in the brain and spinal cord and its overexpression is necessary and sufficient to promote oligodendrocyte differentiation. It functions in part by directly repressing negative regulators of oligodendrocyte differentiation, including transcription factors Sox6 and Hes5. Additionally, microRNA-219 directly represses the expression of PDGFRalpha, FoxJ3, and ZFP238 proteins, all of which normally help to promote oligodendrocyte precursor cell proliferation.

microRNA-219 expression is partly controlled through the N-methyl-d-aspartate receptor (NMDAR) pathway. NMDAR activation selectively downregulates mature miR -219 levels and pharmacological blockade of N-methyl-d-aspartate receptor (NMDAR)-dependent LTP enhanced expression of mature microRNA-219.

Zhao X, He X, Han X, Yu Y, Ye F, Chen Y, Hoang T, Xu X, Mi QS, Xin M, Wang F, Appel B, Lu QR. (2010) MicroRNA-mediated control of oligodendrocyte differentiation. Neuron 65(5), 612-26. [abstract]
Wibrand K, Panja D, Tiron A, Ofte ML, Skaftnesmo KO, Lee CS, Pena JT, Tuschl T, Bramham CR. (2010) Differential regulation of mature and precursor microRNA expression by NMDA and metabotropic glutamate receptor activation during LTP in the adult dentate gyrus in vivo. Eur J Neurosci (4), 636-45 [abstract]

A Busy Month in the Business of microRNA

Chris — Wed, 30 Jun 2010 13:51:34 +0000

BUSINESSWIRE -

June 29^th – Alnylam Obtains Approvals to Initiate Phase I Study with ALN-TTR01 in Patients with TTR-Mediated Amyloidosis (ATTR)

June 29^th – Mirna Therapeutics Publishes Data Demonstrating In Vivo Proof of Concept for miR-34a microRNA Replacement Therapy in Cancer

June 28^th – Reimbursement for Rosetta Genomics’ miRview™ mets Test Now Available in Israel Through World’s Second Largest HMO

June 28^th – Alnylam Scientists and Collaborators Publish Research in Nature Chemical Biology on a Novel Mechanism for Regulation of Gene Expression with Anti-Gene RNAs (agRNAs)

June 23^rd – Santaris Pharma A/S and miRagen Therapeutics, Inc. Form Strategic Alliance to Develop microRNA-Targeted Medicines for the Treatment of Cardiovascular Disease

June 23^rd – Alnylam Biotherapeutics Presents New Data on RNAi Applications in Biotherapeutics Manufacturing

June 22^nd – Isis and Alnylam Provide Update on Regulus’ Strategic Alliance with Sanofi-Aventis

June 22^nd – Sanofi-Aventis and Regulus Therapeutics Form Major Strategic Alliance on microRNA Therapeutics

June 21^st – Mirna Therapeutics Recommended for $10 Million Commercialization Award from the Cancer Prevention and Research Institute of Texas

June 17^th – Alnylam Secures Intellectual Property and Technology for RNAi Applications in Vaccine Research and Development

June 17^th – Alnylam Receives Notice of Allowance from United States Patent and Trademark Office for New Patent Broadly Covering RNAi Therapeutics that Target Mutated Genes

June 7^th – Data Presented at ASCO 2010 by M. D. Anderson Researchers Demonstrate the ability of miRview™ mets to Identify the Most Likely Origin of Metastases in Cancer of Unknown Primary

June 3^rd – Rosetta Genomics Establishes “Rosetta Green” as Majority-owned Subsidiary

Featured Publication – miR-661 expression in SNAI1-induced epithelial to mesenchymal transition contributes to breast cancer cell invasion by targeting Nectin-1 and StarD10 messengers

Chris — Thu, 24 Jun 2010 14:47:23 +0000

Epithelial to mesenchymal transition (EMT) is a key step toward metastasis. MCF7 breast cancer cells conditionally expressing the EMT master regulator SNAI1 were used to identify early expressed microRNAs (miRNAs) and their targets that may contribute to the EMT process. Potential targets of miRNAs were identified by matching lists of in silico predicted targets and of inversely expressed mRNAs. MiRNAs were ranked based on the number of predicted hits, highlighting miR-661, a miRNA with so far no reported role in EMT. MiR-661 was found required for efficient invasion of breast cancer cells by destabilizing two of its predicted mRNA targets, the cell–cell adhesion protein Nectin-1 and the lipid transferase StarD10, resulting, in turn, in the downregulation of epithelial markers. Reexpression of Nectin-1 or StarD10 lacking the 3′-untranslated region counteracted SNAI1-induced invasion. Importantly, analysis of public transcriptomic data from a cohort of 295 well-characterized breast tumor specimen revealed that expression of StarD10 is highly associated with markers of luminal subtypes whereas its loss negatively correlated with the EMT-related, basal-like subtype. Collectively, our non-a priori approach revealed a nonpredicted link between SNAI1-triggered EMT and the down-regulation of Nectin-1 and StarD10 through the up-regulation of miR-661, which may contribute to the invasion of breast cancer cells and poor disease outcome.

Vetter G, Saumet A, Moes M, Vallar L, Le Béchec A, Laurini C, Sabbah M, Arar K, Theillet C, Lecellier CH, Friederich E. (2010) miR-661 expression in SNAI1-induced epithelial to mesenchymal transition contributes to breast cancer cell invasion by targeting Nectin-1 and StarD10 messengers. Oncogene [Epub ahead of print]. [abstract]

Largest microRNA Therapeutics Alliance To Date

Chris — Tue, 22 Jun 2010 18:07:09 +0000

Sanofi-Aventis and Regulus Therapeutics Form Major Strategic Alliance on microRNA Therapeutics

Carlsbad, CA., June 22, 2010 – Regulus Therapeutics Inc. and sanofi-aventis (EURONEXT: SAN and NYSE: SNY) announced today that they have entered into a global, strategic alliance to discover, develop, and commercialize microRNA therapeutics. The alliance represents the largest microRNA partnership formed to date, valued at potentially over $750 million, and includes a $25 million upfront fee, a $10 million future equity investment subject to mutual agreement on company valuation, and annual research support for three years with the option to extend two additional years. The alliance will initially focus on the therapeutic area of fibrosis. Regulus and sanofi-aventis will collaborate on up to four microRNA targets, including Regulus’ lead fibrosis program targeting microRNA-21. sanofi-aventis also receives an option for a broader technology alliance that provides Regulus certain rights to participate in development and commercialization of resulting products. If exercised, this three-year option is worth an additional $50 million to Regulus. (read more… )