A platform for RNA

An information explosion on the number of functional RNA molecules expressed in cells and the mechanisms by which they control gene expression1,2 is driving the formation and funding of biotechs developing oligonucleotide-based therapeutics. Pharmas and big biotechs are carving up the space via partnerships that add multiple nucleic acid-based mechanisms and technologies to their drug discovery toolboxes.

The newest additions to the nucleic acid platform include noncoding RNA targets such as microRNAs and long noncoding RNAs (lncRNAs). Both types of molecule create the opportunity to selectively turn on expression of a given gene, potentially achieving biological and therapeutic outcomes that no other drug platform can.

Small molecules that interfere with the activity of chromatin-modifying enzymes can lead to the activation of many genes, but no small molecule or biologic has been shown to recapitulate the single-gene specificity achievable via the complementary base pairing of oligonucleotide-based modalities.

Although miRNAs and lncRNAs offer new targets and mechanisms, the modalities that target these molecules share one important feature with prior oligonucleotide-based therapeutics-the reliance on interactions between complementary nucleotides. Thus, therapeutics aimed at these new molecules share many of the challenges encountered with other nucleic acid-based agents.

These include delivering the drug to many tissue types, achieving levels of target engagement necessary for therapeutic effects and selecting and validating targets best suited to the modality.

In the beginning

Attempts to use antisense technology as a therapeutic began in the late 1980s. The rationale was clear-find a gene that is causing problems, synthesize a strand of nucleic acid that will bind to the mRNA and use that molecule to shut down the gene. However, a host of practical issues got in the way.

Oligonucleotide-based molecules are not drug like; thus, they require chemical modifications that improve their pharmacokinetics (see "Drug-like chemical modifications to nucleic acids"). In addition, there are multiple delivery challenges. For example, cells need to be coaxed into taking up oligonucleotide-based therapeutics and releasing enough of them from intracellular vesicles to elicit a therapeutic effect without activating an immune response.

Finally, the mechanism of action of some of these oligonucleotide molecules involves enzymatic degradation of the oligonucleotide-target complex. For example, antisense molecules elicit RNase H-mediated degradation of their targets.3 Such mechanisms limit the range of pharmacological improvements that can be made to the molecules before they become unrecognizable to the relevant enzymes.

Two companies, Isis Pharmaceuticals Inc. and Santaris Pharma A/S, have taken the lead in addressing these issues and advancing the technology.

"Isis invented the antisense platform as a viable drug discovery and development approach," said Brett Monia, the company's SVP of antisense drug discovery.

"In the early years, we needed to partner early so that we could build a new technology. However, having a partner develop your drugs, especially something as different as antisense, is much less efficient and less profitable.

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