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MIT: miRNAs Affect Majority of Mammal Genes


Last January, researchers from the labs of Massachusetts Institute of Technology professors David Bartel and Chris Burge published data in Cell indicating that up to a third of the human genome may be regulated by microRNAs.

Now, according to a report in Science, the labs have found that a majority of mammalian genes, while not directly regulated by microRNAs, appear to be nonetheless influenced by the small non-coding RNAs.

In the original paper, Ben Lewis, a graduate student in both Bartel’s and Burge’s labs, “showed that about a third of human genes, roughly, are targeted by micro-
RNAs,” says Andrew Grimson, a postdoc in Bartel’s lab who co-authored the more recent paper. “What we are seeing is that, in addition to the targets of microRNAs, some genes are under selection to avoid being targets of microRNAs, so it’s almost the opposite.”

According to Grimson, his work began with a random selection of evolutionarily conserved miRNA targets — 7-nucleotide long sites on the 3’ UTRs of messenger RNAs — that Lewis had previously identified. “In a tissue culture assay, [we evaluated] how well they worked in response to a microRNA [in order to] get an aggregate feeling for how … much [gene] repression they mediate,” he says. “That was the benchmark.”

Grimson then examined a number of non-conserved miRNA target sites “to see how much repression those mediated,” he says. “If we could show that the non-conserved sites worked about as well as the conserved sites, then that would open up the possibility that the microRNAs are regulating both conserved and non-conserved sites. What I showed was that they worked just as well.”

Grimson notes that “there’s almost an order of magnitude more non-conserved sites of the genome than conserved sites,” changing the picture from one where microRNAs regulate a limited number of conserved sites to one where non-conserved sites, which are 10 times more abundant, also mediate gene repression.

— Doug Macron

Alnylam Pharmaceuticals and Sirna Therapeutics both joined the Nasdaq Biotechnology Index in late November, making them the first RNAi companies to be included on the listing.

Markus Stoffel and researchers at Rockefeller University developed a new class of oligonucleotides, termed antagomirs, that can be used to selectively inhibit microRNAs in vivo. The antagomirs have the potential to act as therapeutic agents by selectively suppressing the expression of disease-associated miRNAs.

Lentigen secured its seed and series A financing from Greenwich Biotech Ventures. The funding will allow the company to launch programs in lentiviral vector development, add commercial-scale manufacturing capabilities, and increase its infrastructure. The company did not disclose financial details.

Sirna Therapeutics began animal testing of a novel type of RNAi molecule, termed “multifunctional” siRNAs, designed to knock down expression of two or more target genes with a single oligo.

At the American College of Rheumatology’s annual meeting in San Diego, Nastech presented the first in vivo data on its experimental siRNA-based rheumatoid arthritis treatment, developed in partnership with the Mayo Clinic. The data indicates that the company’s RNAi drug is able to stop production of human TNF-alpha in mouse models of the disease.


US Patent application 20050266561. Use of interfering RNA in the production of transgenic animals. Inventors: Kevin Wells. Assignee: Revivicor. Filed: November 22, 2004.

According to the abstract, this invention provides “cells and animals, as well as methods of producing cells and animals, that express at least one interfering RNA molecule to regulate the expression of a specific gene or family of genes. The invention further provides novel iRNA molecules, as well as DNA templates for producing iRNA molecules.”

US Patent application 20050267300. Processes and reagents for oligonucleotide synthesis and purification. Inventors: Muthiah Manoharan, Michael Jung, Kallanthottathil Rajeev, Rajendra Pandey, Gang Wang. Filed: April 5, 2005.

“The … invention relates to processes and reagents for oligonucleotide synthesis and purification," the patent application''s abstract states. “One aspect of the … invention relates to compounds useful for activating phosphoramidites in oligonucleotide synthesis. Another aspect of the present invention relates to a method of preparing oligonucleotides via the phosphoramidite method using an activator of the invention,” it adds.

Alnylam Pharmaceuticals began its European phase I trial of an intranasally delivered RNAi drug for the treatment of respiratory illness. The company expects to enroll 57 healthy adult males in the clinical study.
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