Alongside the optimism over RNA interference (RNAi) comes the inevitable question of whether it will fare better than previous RNA-based technologies — antisense and ribozymes — both in the laboratory and in the clinic.

Sirna has switched from ribozymes to siRNA.

Many commentators are placing their bets on RNAi because it taps into a pre-existing control system within the cell and has the potential for greater potency, given that the same small interfering RNA (siRNA) molecules can recycle between different copies of messenger RNA. Single-stranded antisense molecules do not exist naturally, and each one acts only once to block translation of messenger RNA before being degraded. Ribozymes do cleave multiple copies of the same messenger RNA, but their potency remains in question, and there is, as yet, no sign of success as potential therapeutics.

“RNAi is what antisense never was. It's robust and reproducible, and it exists in nature,” says Inder Verma of the Salk Institute for Biological Sciences in San Diego, California. RNAi is “much more active and effective than antisense and ribozymes”, according to Martin Woodle of Intradigm in Rockville, Maryland.

Frank Bennett of Isis Pharmaceuticals in Carlsbad, California, disputes this, at least for in vitro use, saying that “by and large antisense and RNAi are equally potent in cell culture”. For in vivo use, he asserts that RNAi has yet to be fully optimized to justify comparison with antisense. “We're keeping an open mind regarding the therapeutic potential of RNAi. It's too early to make predictions,” he says.

Isis is so far the only company to have succeeded in getting an antisense drug licensed — Vitravene for the treatment of skin disease — and has other antisense products in clinical trials. In contrast, the company formerly known as Ribozyme Pharmaceuticals relaunched in 2003 as Sirna Therapeutics after its most promising antisense candidates proved ineffective in clinical trials. The RNAi technology breakthrough occurred at the right time, according to Nassim Usman, senior vice-president at Sirna.

Others point out the additional concerns that antisense molecules can trigger immune reactions, being larger and ‘foreign’ in composition, compared with siRNA, and can be toxic. But Bennett asserts that Isis has modified its antisense products to minimize these potential problems.

NeoPharm in Illinois is maintaining a stake in both approaches. While results from animals show the overall effectiveness of RNAi to be “very much better than with antisense”, according to chief scientific officer Imran Ahmad, and to require a fivefold smaller dose, the company intends to compare its lipid-based delivery system for antisense and RNA side-by-side in the clinic.

JULIE CLAYTON