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NIH Awards $1.2M in Three SBIR Grants to Fund Projects Studying miRNA Inhibition, Detection

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By Doug Macron

The National Institutes of Health this month doled out more than $1.2 million in three Small Business Innovation Research grants to help a trio of companies develop microRNA- and miRNA-inhibition and -detection approaches for clinical applications.

The first grant went to Hocus Locus, a spinout of the University of Albany developing a novel technology, structurally interacting RNAs, which the company claims can act like nanoswitches to detect miRNAs in vivo and induce target protein translation.

“While there are numerous methods to quantify miRNAs in vitro, we are not aware of any method that allows for in vivo analysis,” the company states in its grant abstract. “The ability to observe specific miRNA generation in living single cells without requiring the destruction of the cell would be a significant tool.”

RNA-binding proteins normally associate with a 3' stem-loop structure to help translate an upstream coding region, according to the abstract. However, “it is possible to modify the mRNA to modulate translation of the reporter gene by controlling the binding of RBP."

This is done by "altering the natural stem-loop structure so that it does not form unless an additional RNA … binds and stabilizes the functional structure by base-pairing with the flanking regions of the custom designed stem-loop,” the abstract said.

With funding from the NIH, Hocus Locus aims to evaluate this approach in vitro, then measure the effect on translation and determine whether the approach would be effective in vivo.

Hocus Locus expects that the technology could have diagnostic applications “anywhere that miRNA expression levels are an indicator of disease, cell or tissue type, or condition,” and may even have potential as an alternative to gene therapy, the abstract states.

The grant began on Sept. 1 and runs until the end of August, 2012. It is worth $293,557.

The second grant was awarded to Bioo Scientific to help it develop a method to sequence simultaneously large numbers of small RNAs, including miRNAs.

“Currently there are no discovery-based, rapid-multiplexed methods available to simultaneously measure miRNA expression in several samples or tumor tissues,” the grant's abstract states. “Next-generation sequencing technologies are, in principle, very well suited for high-throughput sequencing of small non-coding RNAs.”

However, they can be time-consuming and expensive when used with large numbers of small-RNA samples.
To address this issue, Bioo is developing a “multiplex strategy to simultaneous sequence large numbers of small RNAs by indexing using sample-specific short identifying nucleotide sequences,” it said in the abstract.

This approach is expected to overcome issues such as enzymatic sequence biases that may “prefer certain transcripts,” as well as the impact that indexing at different depths has on small RNA profiles.

Indexing offers the advantage of measuring base error rate, it added. Further, it allows the user to perform “cross-genomic studies, time courses, [and] drug-induced cellular experiments, and monitor day-to-day expression variability between samples.”

Ultimately, Bioo aims to develop a kit for minimally biased, highly indexed small RNA libraries for massively parallel sequencing that can allow the same libraries to be easily interrogated by real-time PCR.

The company's grant runs from Sept. 1 until April 30, 2012, and is worth $235,725.

The final award was given to preclinical contract research organization RxGen to help it study the effects of an miR-208 inhibitor in monkeys, with the goal of advancing an agent targeting the heart-specific miRNA into clinical trials.

Miragen Therapeutics, which is developing a miR-208 antagonist as a treatment for chronic heart failure, is a collaborator on the grant.

Research led by Miragen has shown that miR-208 is co-expressed with 1-myosin heavy chain, and is associated with cardiomyocyte hypertrophy, fibrosis, and the expression of beta-MHC in response to stress and hypothyroidism.

“Mice homozygous for the miR-208 deletion are viable and do not display obvious abnormalities in size, shape, or structure of the heart but … appear resistant to cardiac stress, as shown by a lack of hypertrophy and fibrosis following thoracic aortic banding,” RxGen noted in the grant's abstract.

Follow-on preclinical experiments show that locked nucleic acids targeting miR-208 can decrease cardiac levels of the miRNA, and preserve cardiac function in a rodent model of heart failure, the company added.

Looking to take these findings closer to human applications, RxGen aims to examine the biodistribution, pharmacokinetics, and pharmacodynamics of systemically delivered inhibitors of two isoforms of miR-208 in monkeys.

“Additionally, we will induce chronic hypertension to define microRNA changes associated with cardiac remodeling and dysfunction in the setting of congestive heart failure,” RxGen said in the abstract. “Characterization of the pathophysiology will include determination of cardiac tissue expression of miR-208 isoforms, myosin expression, cardiac remodeling, and extensive evaluation of functional deficit post-occlusion.

Demonstrating hypertrophy and fibrosis in the miR-208-expressing myocardium, along with pharmacokinetic and pharmacodynamic data, will permit “compelling efficacy assessments ... to enable rapid advancement” of a miR-208-specific antagonist into investigational new drug application-enabling toxicology studies and clinical trials.

The one-year grant began on Sept. 1 and is worth $718,304.


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