By Eric Bender
Since its discovery 16 years ago, researchers have been eyeing RNA interference (RNAi)—a natural process of posttranscriptional silencing of genes by small fragments of the nucleic acid—for its potential in therapy, especially in treating forms of cancer and other diseases that are particularly hard to address with existing drugs. But the path of such RNAi therapies to the clinic has been nothing short of a pharmaceutical roller-coaster ride.
Andrew Fire and Craig Mello first demonstrated RNAi in C. elegans in 1998, a discovery recognized in 2006 when they won the Nobel Prize in Physiology or Medicine.1 Interest exploded in 2001 when biochemist Thomas Tuschl and colleagues at the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany, demonstrated potent and specific RNAi silencing in mammalian cells.2 Before long, researchers around the world were using these principles to selectively knock down the expression of genes of interest in cell lines and animal models.
“RNAi rapidly became a workhorse technique for basic research,” says Douglas Fambrough, chief executive officer at Dicerna Pharmaceuticals in Watertown, Massachusetts. “It was really easy to get it to work, and it worked really well.”
At the same time, the scientific community began to develop a growing interest in RNAi therapies. Among its benefits, RNAi can prevent the proteins actually driving an illness from being translated, which avoids the need to attack the disease somewhere downstream in a molecular cascade, as small-molecule drugs and biologics often do, says Akshay Vaishnaw, chief medical officer at Alnylam Pharmaceuticals in Cambridge, Massachusetts. “Why not turn them off at their source?” he asks.
RNAi can provide greater target specificity than small molecules and inhibit the expression of proteins that lack the enzymatic pocket necessary for binding small-molecule drugs, says Mark Murray, president of Tekmira Pharmaceuticals in Vancouver, British Columbia. RNAi can also target proteins that can’t be reached directly by monoclonal antibodies because of their intracellular location.