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Feb 06, 2014
 |  BC Innovations  |  Tools & Techniques

RNA is for activation

Although siRNA-based therapeutics have recently been clinically validated as a strategy to knock down gene expression, a lesser-known function for short double-stranded RNAs is their ability to turn on the expression of target genes. Now, an academic team sponsored by MiNA Therapeutics Ltd. has found a way to attack liver cancer in rats by using a short activating RNA to upregulate expression of a tumor suppressor,1 and the company plans to advance the program to the clinic this year.

siRNAs target mRNA coding regions and are used to knock down gene expression via targeted cleavage by an RNA-induced silencing complex (RISC).The clinical development of this strategy was pioneered by Alnylam Pharmaceuticals Inc., which last month entered into a major collaboration to develop products with the Genzyme Corp. unit of Sanofi.2

At least 12 additional companies are pursuing the development of RNAi-based therapeutics, one of which, Dicerna Pharmaceuticals Inc., went public last week and saw its stock more than triple in its first day of trading. The preclinical-stage company ended the week with a market cap of

$683.7 million.

Small activating RNAs (saRNAs) are structurally related to siRNAs, but instead of targeting mRNA, they target regulatory regions of DNA upstream of genes of interest. This can lead to increased gene expression, though the precise mechanisms of action for saRNAs are poorly understood.

MiNA CEO Robert Habib told SciBX, "The beauty of saRNA is that well-established oligonucleotide designs can be used as triggers for gain of function. That allows MiNA to leverage years of pharmaceutical development, from assays to delivery, which have enabled a robust pipeline of 'loss-of-function therapeutics'."

These advances include the development of lipid nanoparticle formulations that enable efficient short double-stranded RNA delivery to the liver in humans.

Thus, MiNA set out to design a liver-targeted saRNA to treat hepatocellular carcinoma (HCC).

Prognosis for patients with HCC is poor because a majority have advanced disease at the time of diagnosis, which impairs liver function...

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