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Inhibiting the Inhibitor - miRNAs as Therapeutic Drug Targets

Inhibiting the Inhibitor - miRNAs as Therapeutic Drug Targets

This is the fifth in a series of posts analyzing Rosetta Genomics stock.

Most drugs that target proteins work by inhibiting the protein’s function. It’s simply a function of biology; it’s much easier to design a drug that will interfere with a protein’s function than it is to make it overactive. But sometimes (many times actually), it would be nice to make a protein overactive in order to fight a disease. For instance, overexpressing a tumor suppressor might kill tumor cells. Sometimes this is possible if the protein has a natural protein inhibitor. By inhibiting the inhibitor, you can stimulate the protein whose function you want to increase.

Since miRNAs are natural inhibitors of protein expression, inhibiting them causes increased activity of the protein. In cancers, miRNAs are often overexpressed, so they make good potential drug targets. Rosetta Genomics is working with Isis Pharmaceuticals, who has experience with inhibiting RNA molecules in vivo, on miRNA inhibitors to treat liver cancer. The inhibition is carried out by complementary synthetic molecules that bind to the miRNAs and prevent them from binding to the mRNA, resulting in expression from those mRNAs. To date they have discovered 5 miRNAs that have elevated levels in tumor samples compared to normal tissue. They are currently trying to inhibit these miRNAs in tissue culture cells (in vitro) before they move into mouse models (in vivo). I’m a little worried that the level of miRNA inhibitors required for them to see an effect on tumor growth might be greater than is achievable in vivo, but Isis Pharmaceuticals has been able to inhibit miRNAs in the liver of mice, so perhaps my fears are unwarranted.

If anyone reading this is at the AACR meeting in LA this week, stop by Rosetta’s poster and get the current information on the project. Then leave a comment or e-mail me at hotmail.com with biologyfool before the @ with the scoop.

Rosetta Genomics is also working on miRNA inhibitors for infectious disease. Some viruses encode miRNAs and others cause overexpression of human miRNAs after infection. Both of these can serve as potential targets to attack the infection. For instance, they have demonstrated in vitro that the inhibition of Epstein-Barr virus (EBV) microRNAs inhibits viral replication. With collaborators (mostly in academia), they are also working on finding miRNA inhibitors to fight infection of HIV and hepatitis C virus.

All of their research on therapeutics is still in initial stages. Since microRNA inhibitors are fairly innocuous, Rosetta Genomics might be able to do a combined phase 1/2 trial. But even in that case, the therapeutics are still many years away. Hopefully some of their diagnostic test will gain approval and fund their clinical trials.

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