By James DeGiulio —

When Andrew Fire and Craig Mello (at right) unraveled the mechanism of RNA interference (RNAi) and were awarded the Nobel Prize in 2006 for their efforts, RNAi was predicted to become the next great source of new therapeutics.  Pharmaceutical companies moved quickly to devote research funding and personnel to developing what appeared to be a novel way to target nearly any protein involved in nearly any disease.  However, five years — and billions of dollars in research and development — later, it appears that RNAi is falling out of favor in the industry, which is moving away from investing in potential RNAi therapeutics, according to a recent New York Times article ("Drugmakers’ Fever for the Power of RNA Interference Has Cooled").  Despite the nearly universal belief that at a certain point RNAi will make it to the market, the efficiency of RNAi delivery has thus far limited its therapeutic potential.  Industry executives claim that alternatives to RNAi that are closer to producing marketable drugs have taken priority, including conventional drugs, monoclonal antibodies, and even older antisense gene silencing technology.

RNAi was first discovered in 1998 in the nematode worm Caenorhabditis elegans and later found in a wide variety of organisms, including mammals.  Research development moved quickly, and by 2005, three drugs were ready for clinical trials.  Since then, however, two of the three trials have already been dropped due to inefficient delivery.  The third, targeting respiratory infection, has shown some signs of effectiveness, but conclusive trials are only now under way.  Achieving efficient delivery of RNAi molecules has been the largest obstacle to realizing the therapeutic potential of RNAi, an obstacle that has also limited gene therapy applications.  Drugs working through the RNAi mechanism have been shown to successfully silence genes, but it has been difficult to deliver these drugs to the cells where they are needed.  One major problem is that RNA is quickly degraded in the bloodstream, and even if the RNA can reach the target cells in the body, it has trouble entering the cells.  Yet another obstacle is the immune response that double-stranded RNA particles can provoke.  To address these issues, scientists have developed RNA chemical modifications which prevent degradation in the bloodstream and avoid immune responses, but achieving efficient and reliable delivery of RNAi remains elusive.

Within the past year, some big players in the biotech industry have pulled the plug on development of RNAi therapeutics.  In November 2010, Roche announced the end of its efforts to develop drugs using RNAi, after it had invested half a billion dollars in the field over four years.  In January 2011, Pfizer decided to shut down its 100-person unit working on RNAi and related technologies.  Abbott Laboratories has also ended its RNAi drug development work.  Partnerships have also decreased, as big pharma companies have been increasingly hesitant to invest capital in smaller companies that specialize in RNAi.  Alnylam Pharmaceuticals, widely considered the leader among these companies, cut a quarter of its work force late last year after Novartis decided against partnership.

History may indicate that the RNAi hype is just dying down, and more realistic expectations are now taking hold.  It is not unusual for the initial enthusiasm for a new technology to wane as the technology slowly is perfected.  A prime example is monoclonal antibodies, which took twenty years to translate into blockbuster drugs like Avastin and Humira.  Indeed, regardless of the decisions of big pharma, interest in RNAi technology still remains.  In early February, two midsize European drug companies signed small deals to explore development of RNAi drugs.  Also, despite no clear proof that a drug using RNAi can effectively treat a human disease, about a dozen RNAi drugs in clinical trials are currently pending, which is more than ever before.