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Asuragen, Mirna Therapeutics, Alnylam Pharmaceuticals, Proceedings of the National Academy of Sciences

Asuragen Officially Launches miRNA Rx Spin Out
Asuragen this week announced that it has spun out its microRNA-based therapeutics intellectual property into a new company called Mirna Therapeutics.
Specific details about the structure and focus of Mirna were not disclosed.
“The discovery of miRNAs represents a paradigm-changing event in biology and medicine of a magnitude that only occurs once every decade or two," Asuragen CEO and CSO Matt Winkler said in a statement. “They likely will become a major new class of drugs.”
As reported by RNAi News in January, the new company is initially being funded with $3 million from Asuragen (see RNAi News, 1/24/2008).

Alnylam Reports Preclinical Data on Three Programs
Alnylam Pharmaceuticals this week reported preclinical data from three of its preclinical drug-development programs including liver cancer, Ebola virus, and progressive multifocal leukoencephalopathy.
The data were presented at last week’s RNAi, MicroRNA, and Non-Coding RNA Keystone Symposium, Alnylam said.
Alnylam’s liver cancer drug candidate, ALN-VSP, comprises two siRNAs targeting vascular endothelial growth factor and kinesin spindle protein, respectively. According to the company, when delivered using Protiva Biotherapeutics’ stable nucleic acid-lipid particles, the siRNAs triggered significant dose-dependent silencing of both KSP and VEGF derived from the human tumor in a mouse model.
Additionally, a reduction I tumor growth as measured by quantification of a tumor-specific gene and a drop in the size of liver tumors in VSP-treated animals as observed by gross pathology were observed, Alnylam said.
Alnylam expects to file an investigational new drug application for ALN-VSP or its hypercholesterolemia candidate, which targets proprotein convertase subtilisn/kexin type 9, sometime this year.
As for its Ebola program, Alnylam said that siRNAs targeting a viral gene and optimized with a lipid particle delivery system developed in collaboration with Tekmira Pharmaceuticals led to a greater than 95 percent decrease in viral titer in to mice infected with Ebola. This treatment was also able to protect mice and guinea pigs from lethal Ebola infection.
Alnylam is working with the US Army on the development of the Ebola drug (see RNAi News, 4/13/2006).
Alnylam’s PML program stems from a 2006 alliance with Biogen Idec (see RNAi News, 9/21/2006), which markets the multiple sclerosis drug Tysabri. First approved in 2004, Tysabri was expected to be a major revenue generator, but was pulled from the market after being associated with a limited number of cases of PML, two of which were fatal.
Alnylam said this week that RNAi compounds targeting different JCV transcripts have been identified and showed potent inhibition of secondary PML infection in vitro, both before and after infection.
“Because there is no established animal model of PML, Alnylam is delivering its RNAi therapeutic to normal oligodendrocytes, the primary site of JCV infection in vivo,” the company said.
Alnylam also presented data from its hypercholesterolemia program, but these data had already been presented at a scientific conference last year (see RNAi News, 10/11/2007).

Study Finds Herpesviruses Use miRNA to Silence Genes During Latency
New research suggest that microRNAs help viruses in the herpesvirus family hide out and remain dormant in the host body for months or even years between symptomatic infections, GenomeWeb Daily News, an RNAi News sister publication, reported this week.
American and Swiss researchers used a quantitative algorithm to predict viral miRNA sites of action based on their sequence. The algorithm predicted that a human cytomegalovirus miRNA called miR-UL112-1 binds to and regulates mRNA for genes suppressed during viral latency — a finding the team verified experimentally. The results, which appeared online this week in the Proceedings of the National Academy of Sciences, also suggest that other herpesviruses use similar mechanisms while seemingly dormant.
“We propose that herpesviruses use a common miRNA-based strategy to maintain latency,” the authors wrote.
The herpesviruses are a family of relatively large, double-stranded DNA viruses that infect vertebrates. Common examples include herpes simplex virus 1, human cytomegalovirus, Epstein-Barr virus, and Kaposi’s sarcoma-associated virus. These viruses remain latent or dormant for long stretches of time, during which there is only a small amount of viral replication.
The viruses resurface during a so-called lytic replication stage, causing infection. Lytic replication itself has three stages: an immediate-early stage, which prepares gene products used in infection; an early stage, involving viral DNA replication; and a late stage, during which the virus’ structural proteins are produced.
Senior author Arnold Levine, a researcher at the Simons Center for Systems Biology at the Institute for Advanced Study in Princeton, NJ, and his colleagues suspected that some herpesvirus miRNAs might inhibit viral genes, keeping viruses in a quiescent, latent state, according to GenomeWeb Daily News. To test this, his team developed a quantitative algorithm to predict just which genes the herpes virus miRNAs target.
“[O]ur algorithm uses a combination of analytical expressions and Monte Carlo simulations to determine exact probabilities that predicted miRNA targets would occur by chance,” the authors wrote.
When they used this algorithm to evaluate miRNAs in human cytomegalovirus, the researchers found that it predicted that an miRNA called miR-UL112-1 would bind the 3’ untranslated region of IE1 mRNA. IE1 is a major product of the HCMV intermediate-early transcriptional locus needed for efficient viral replication.
Indeed, when the researchers tested miR-UL112-1 experimentally, it did seem to bind to and regulate the IE1 UTR. For instance, they found that IE1 protein synthesis was significantly higher in viruses that were modified to lack miR-UL112-1 interactions with IE1 mRNA than it was in wild type viruses 48 hours after infection — even though there were no detectable differences in the IE1 mRNA levels.
Along with these immediate-early genes, the algorithm also predicts that herpesviruses contain miRNAs that target other viral functions such as replication, apoptosis, and host immune system evasion.
Similarly, in an article published last November in the journal PLoS Pathogens, senior author Jay Nelson, a microbiologist and virologist at the Oregon Health Sciences University, and his colleagues used comparative bioinformatics to show that miR-UL112-1 targeted three viral mRNAs, including the major immediate-early gene. They also suggest that the miRNA regulates genes involved in replication.
Though miRNAs are not conserved between different herpesvirus sub-families, the algorithm used in the latest research predicts that many herpesviruses encode miRNAs that suppress their own genes during early infection.  
“We propose that herpesviruses use microRNA-mediated suppression of immediate-early genes as part of their strategy to enter and maintain latency,” the authors wrote. “[I]f miRNAs are indeed central agents responsible for the maintenance of latency, this would explain the mysterious failure to detect proteins in the latent stage of [herpes simplex virus-1].”

The Scan

Pig Organ Transplants Considered

The Wall Street Journal reports that the US Food and Drug Administration may soon allow clinical trials that involve transplanting pig organs into humans.

'Poo-Bank' Proposal

Harvard Medical School researchers suggest people should bank stool samples when they are young to transplant when they later develop age-related diseases.

Spurred to Develop Again

New Scientist reports that researchers may have uncovered why about 60 percent of in vitro fertilization embryos stop developing.

Science Papers Examine Breast Milk Cell Populations, Cerebral Cortex Cellular Diversity, Micronesia Population History

In Science this week: unique cell populations found within breast milk, 100 transcriptionally distinct cell populations uncovered in the cerebral cortex, and more.