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With NIH Funding, Hocus Locus Aims to Develop Novel microRNA Inhibitors

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NEW YORK (GenomeWeb) – Having just secured its second small business grant from the National Institutes of Health, University at Albany spinout Hocus Locus is aiming to further develop a novel microRNA inhibition technology initially for research applications and, ultimately, as a therapeutic modality.

The approach is based on so-called structurally interacting RNAs, or sxRNAs, which the company believes are part of a post-transcriptional regulatory mechanism that controls RNA binding protein (RBP) interactions with messenger RNA.

Typically, RBPs associate with a 3' stem loop structure to enable translation of an upstream coding region, according to Hocus Locus. However, it is possible to modify mRNA to modulate translation of a gene by controlling the binding of RBP. Specifically, the natural binding site of the RBP, usually a stem loop structure, can be altered in such a way that it does not form unless a specific miRNA binds and stabilizes it by base pairing with the flanking regions of the engineered stem loop.

As University at Albany researcher and sxRNA inventor Scott Tenenbaum explained in a recent paper detailing the technology, "unlike traditional miRNA/mRNA double-stranded duplex formation, these trans three-way junctions … result from the splinting of the miRNA discontinuously across the flank region of the mRNA located at the base of the stem loop element."

Though similar to those that are well established in ribosomal RNA, the sxRNA three-way junctions are formed in trans from two independent RNAs, he added in the paper. "This interaction represents a potentially new post-transcriptional regulatory role" for non-coding RNA.

Initially, Tenenbaum and Hocus Locus had envisioned the sxRNA technology as a tool to measure miRNA activity in vivo, with the molecules turning on the expression of a reporter gene in the presence of an miRNA of interest.

According to Hocus Locus CEO Ted Eveleth, the company and its collaborators were able to do just that, demonstrating in cell lines that sxRNAs could increase reporter gene expression of mRNA by more than an order of magnitude when an unnamed miRNA was present. These data, he noted, are being prepared for publication.

But with the support of a new one-year, $224,609 grant from the NIH, along with an undisclosed cash infusion from investment group Eastern New York Angels, Hocus Locus has set its sights higher and is looking to develop sxRNAs as miRNA inhibitors.

Although a number of technologies exist for miRNA silencing, the effects of these synthetic molecules can be variable and they often trigger undesirable immune responses, Eveleth told Gene Silencing News.

In contrast, an sxRNA blocks an miRNA target by "creating more places for that miRNA to bind in the cell and decreasing its functional role elsewhere, [an interaction that] is more natural than other inhibitor designs" and should help avoid interferon induction, he said.

At the same time, the presence of a stem loop within the bounds of the miRNA interaction prevents cleavage by Dicer, and the flanks of the stem loop can be made perfectly complementary to an miRNA of interest to enhance binding. Meanwhile, the three-way junction structure offers increased stability.

While Hocus Locus views these features of the sxRNA technology as supportive of its use as a research tool, the company sees therapeutic potential, as well, since the molecules can be designed to include a custom gene-coding region that produces a protein of interest.

In addition to blocking an miRNA involved in a disease process, sxRNAs could also be used, for instance, to make apoptosis-inducing proteins exclusively in cancer cells based on their unique miRNA expression profiles, Eveleth said.

The technology could also be used to enhance gene therapy by expressing a missing protein in only certain cell types, or to express a regenerative protein in damaged organs by adapting sxRNAs for miRNAs only expressed in target tissue, he added.

At the moment, however, such applications remain theoretical, Eveleth conceded, noting that Hocus Locus is still in the process of generating proof-of-concept data for the sxRNA approach as it searches for a CSO to help guide its scientific efforts.

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