Getting gene therapy under control: ARIAD Pharmaceuticals, Inc.

When expression just can’t wait, ARIAD has the RAPID system, in which a drug frees pre-made protein from an aggregate, so it can be secreted promptly into the bloodstream.“We had devised a (rapid delivery) scheme,” says Clackson, “but the key thing we needed was a conditional aggregation domain (CAD). By pure chance we discovered such a protein. It sat on the shelf for a while until we realized that it would work with RAPID.”The CAD (now called FM) was one of the FKBPs engineered with a hole to accommodate AP1903. FM was the one variant that, unexpectedly, gave a positive two hybrid when paired with itself. The aggregation was dissociated by a monomeric version of AP1903.Several FM domains strung together cause a protein to aggregate in the endoplasmic reticulum unless the monomer drug is added. Protein (e.g. insulin) release can be detected by 15 min after drug addition, and peaks within 2 h. The system is particularly well suited to proteins that must be pulsed rapidly to be effective, such as parathyroid hormone for osteoporosis or beta-endorphins for chronic pain.RAPID is far from the clinic, but has generated a Science paper. So is science triumphing over business? Clackson thinks not. “We’ve got a more ruthless product focus than we’ve had in the past,” he says.And Berger has no regrets about the good science. “The challenges have been scientific,” he says. “These have been hard programs to pursue. If you overcome these challenges you create something of great value, and I think we are there now.”