Now investigators are looking for ways to turn this powerful new role for RNA into corporate profits. Virtually all drug companies already use RNA interference as a tool for drug discovery. One of the most popular strategies for finding new drug targets involves knocking out-or disabling-genes one by one to see what happens. If, for example, a diseased animal can be cured by knocking out a particular gene, that gene’s protein could make a good drug target. Using small interfering RNAs, it turns out, can radically speed this process. Instead of spending months or years to engineer a knockout, researchers use the RNAs to specifically and rapidly shut off a gene. They can also observe whether turning off the protein-as a drug would-causes side effects. The process takes place “in a matter of days, instead of a year,” says Christophe Echeverri, CEO of Cenix BioScience, a biotech company in Dresden, Germany.
In the ultimate application, small interfering RNAs might themselves be drugs: rather than blocking a particular protein, as standard drugs do, RNAi would prevent the protein from ever being made. Last June, MIT’s Sharp showed that such RNAs, targeted to key viral and human genes, could stop HIV infection in cells grown in the lab. In one experiment, the researchers mixed HIV-infected cells with small interfering RNAs targeted to viral genes. The RNAs halted viral reproduction. Sharp’s group also mixed uninfected cells with small interfering RNAs targeted to CD4, a protein on the surface of cells through which HIV gains entry. The researchers showed that the RNAs did decrease production of CD4. Two and a half days later, they exposed RNA-treated cells and untreated cells to HIV. The virus infected four times as many untreated cells.
Despite the encouraging results, for the time being RNAi drugs are still in the dream stage, says Sharp. But Sharp considered the early promise tantalizing enough to cofound-with Zamore, Tuschl, and two other scientists-Alnylam Pharmaceuticals in Cambridge, MA, to develop such drugs. The company was barely off the ground when it secured $17 million in venture capital funding last July.
Making RNAi drugs, though, won’t be easy. For one thing, no one has found methods suitable for administering the RNAs to humans. “There’s a delivery problem. It’s as simple as that,” says Harvard University chemist Stuart Schreiber. “Getting nucleic acids to their target tissues [is] an unsolved problem in medicine.” RNAi therapy is essentially gene therapy, Schreiber says, and it will face the same problems-inefficiency, ineffectiveness, and immunological side effects-that have stalled that field since 1999, when Jesse Gelsinger died during a gene therapy trial at the University of Pennsylvania. Doctors there used modified viruses as delivery vehicles, or “vectors,” to shuttle DNA into the teenager’s cells. Gelsinger’s immune system responded massively-and fatally.
Sharp says the hope is that small interfering RNA might not need vectors to reach its target, thus avoiding most of the pitfalls associated with DNA-based gene therapy. But that scenario is far from certain. “Can you modify RNAs to make them more stable [and] to make them be taken up more efficiently by cells?” Sharp asks. “We don’t know.”