RNA Revolutionaries

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"This is a gift from heaven." So said MIT biologist Phillip Sharp, Nobel laureate and founder of Alnylam Pharmaceuticals, to The New York Times in 2003. Sharp was rhapsodizing about RNA interference, or RNAi, the swift and efficient way a cell protects itself by dispatching tiny snippets of RNA to silence harmful gene expression. Researchers at Harvard had just succeeded in using RNAi to "turn off" a worm's genes, one at a time, to identify which causes obesity. And given that the human RNAi pathway is very similar to a worm's, this was yet another in a series of fast affirmations of RNAi's therapeutic promise. While gene silencing (through approaches such as antisense) has so far proved dicey, and RNA research has so far yielded a decade's worth of failed drugs, RNAi is sparking visions of a revolutionary technology spitting out one new highly specific compound after another—almost as fast as the Human Genome Project can name disease targets.

Today, just five years since Sharp's pronouncement and only a decade since the discovery of RNAi, the first RNAi drug, Opko Health's controversial bevasiranib, for wet age-related macular degeneration (AMD), is enrolling Phase III, with a competitor or two right behind.Moreover, in these tough financial times, RNAi R&D shops are flush with cash. Kalorama Information estimates that the best case market for RNAi and other nucleic acid (NA) therapies is worth $210 billion, led by neurological diseases ($83 billion), cancer ($44 billion), and autoimmune diseases ($42 billion). Since 2005, leader of the pack Alnylam has inked milestone deals ranging from $700 million to more than $1 billion with Novartis, Roche, and Takeda, while Merck bought Sirna Therapeutics flat out for $1.1 billion.

Yet despite the enthusiasm, the "gift from heaven" remains largely an article of scientific faith. While direct delivery to the eye and the lungs has been achieved, systemic RNAi delivery (intravenous or subcutaneous, for example), which would open up RNAi for many more diseases, is far more challenging. (Significant progress has been made for systemic delivery to the liver, tumor tissues, and kidneys.) "RNAi will not be validated as a therapeutic until there is a market launch of a systemically delivered product," says Barbara Bolten, a Decision Resources biotech analyst. "If this milestone is achieved, there will be an explosion of interest and investment equal to what we see in biologics today."

The Science of Gene Silence

The discovery of RNA interference is the latest triumph in the resurgence of the RNA molecule as a focus of intense scientific interest. Kicked to the curb by the mid-century discovery of DNA, nondescript, single-stranded RNA was long viewed as subsidiary to its double-helix master, shuttling production orders to the cell's protein-making refineries. In this scenario, proteins, designed by the DNA, carry out most of a cell's function, including the on/off switch for genes. (For another view of recent RNA research, see "That Thing about RNA".)

"There's been a huge leap in our understanding of RNA," says Jim Niedel, a managing director at New Leaf Venture Partners and former chairman of Sirna Therapeutics. "Just about everything that DNA, enzymes, and proteins do, RNA was basically there first."

Biologists Craig Mello, of the University of Massachusetts, and Andrew Fire, of Stanford, discovered RNAi in 1998 while studying the worm genome. The simple, elegant process by which RNA blocks gene expression was gradually worked out: As double-stranded RNA (dsRNA) enters a cell, it is recognized by an enzyme dubbed Dicer, which chops the long strands into many smaller units, 20 to 25 nucleotides long, called small interfering RNAs (siRNAs). These siRNAs are the stars of the show. Like dsRNAs, they're two-stranded. In the cell, the strands are separated and the active strand is loaded into the Slicer complex which is then guided by the small RNA toward its target: a long strand of messenger RNA (mRNA) carrying coded information from DNA to the cell's protein-making mechanism.

When Slicer reaches the mRNA, the siRNA finds the sequence of nucleotides that is its exact mirror opposite and binds to it—a perfect but fatal fit. For then Slicer, still attached to the siRNA, cuts the long mRNA in half. No longer intact, the mRNA appears to the cell as alien—and is pulverized. No messenger, no message, no protein. As aberrant protein function accounts for most diseases, interfering with such protein expression is predicted to have a therapeutic benefit.

Mello and Fire's eureka spurred a flurry of efforts to engineer the process to target specific genes. In a sign of delivery challenges awaiting them, researchers repeatedly met with failure, as the process triggered immune defenses that destroyed the RNA. Then in 2001, Thomas Tuschl, at Germany's Max Plank Institute, along with colleagues at MIT, UMass, and Harvard, hit upon the idea of making smaller siRNA triggers. At 20 or so nucleotides in length, the molecule hit all its marks.

Drug R&D couldn't be more efficient, at least on paper: ID a gene target and its nucleotide sequence (which will carry the information for the target messenger RNA), and then create a strand of RNA in the reverse order to trigger the process.

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