The Second Coming of RNAi

Now showing clinical progress against liver diseases, the gene-silencing technique begins to fulfill some of its promises.

By Eric Bender | September 1, 2014

http://www.the-scientist.com/?articles.view/articleNo/40871/title/The-Second-Coming-of-RNAi/

THE ART OF SILENCING: Small interfering RNA molecules are incorporated into an RNA-induced silencing complex where they bind and degrade target messenger RNAs (yellow with red rings). Taking advantage of this natural RNA interference (RNAi) pathway, researchers are developing therapeutics for liver-based diseases, viral infections, cancer, and more.© MEDI-MATION LTD/SCIENCE SOURCE

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.

Around 2005, the field entered what independent biotech consultant Dirk Haussecker refers to as an “era of irrational exuberance” surrounding the new approach. Major pharmaceutical companies invested several billion dollars in RNAi therapeutics “regardless of technical obstacles,” says Haussecker, who specializes in RNAi and other RNA-based therapies. Numerous biotechs jumped into RNAi therapeutics—especially for diseases with well-validated genetic targets not addressed by current treatments.

But early clinical trials generally failed to meet expectations. Most strikingly, Miami, Florida–based pharmaceutical and diagnostics company OPKO Health shut down its Phase 3 trial of an RNAi treatment for wet macular degeneration in 2009 after the intervention failed to meet the trial goals. Other RNAi-based drugs provoked strong innate immune reactions, failed to deliver patient benefit, or both.

The disappointments hung over the field for the next few years, a period Haussecker refers to as “the era of doubts and despair.” In the face of broader industry turmoil, RNAi programs often were among the first to get chopped. In 2010, Roche, which had invested about $500 million in RNAi, shut down its internal research program. The following year, Pfizer and Abbott also pulled out of in-house RNAi development, and Merck shuttered the RNAi laboratory it had acquired in 2006 with its $1.1 billion purchase of Sirna Therapeutics.

The good news is that the RNAi roller coaster has been on a fairly steady climb for the past few years, following refinements in RNAi targeting and delivery. The number of early clinical successes is climbing, and many in the field expect the next few years to see the approval from the US Food and Drug Administration (FDA) for numerous RNAi drugs now in the pipeline. “There are some who say that the RNAi cup is half empty,” says Alnylam’s Vaishnaw, “but the regulatory authorities are not in that group. Our early development work is extremely compelling to regulators and they partner vigorously because of that.” (The FDA declined to comment on its assessment of RNAi therapeutics as a new class of drugs.)

Speculation about future therapy approvals aside, there’s no question about the field’s recent scientific progress, says David Lewis, chief scientific officer at Arrowhead Research in Madison, Wisconsin. “The days of wondering whether RNAi will be effective in humans are behind us.”