Proteostasis Eyes Technique to Keep Your Proteins in Balance

Xconomy Boston — 

One of those foggy concepts from eighth-grade biology came back to me the other day when I spoke with David Pendergast. It’s homeostasis, the idea that the human body naturally makes constant adjustments on the fly to maintain a proper balance of things like body temperature, water, or salt in your system.

Pendergast, the CEO of Cambridge, MA-based Proteostasis Therapeutics, is attempting to take advantage of new insights in biology that may enable scientists to promote or restore the homeostasis of proteins—molecules that are key players in every tissue and organ in the body and which can cause a host of problems when they’re out of whack. Restoring protein homeostasis might mean revving up the protein machinery that normally does the job of sweeping up degraded proteins; this machinery can break down as we age, causing diseases like Alzheimer’s or Parkinson’s. Or it could help patients with rare genetic disorders, such as Huntington’s disease, who might just need a nudge to their protein networks to keep their symptoms at bay, Pendergast says.

Proteostasis recently raised a whopping $45 million in its initial round of financing, from HealthCare Ventures, Fidelity Biosciences, New Enterprise Associates, Novartis Option Fund, and Genzyme Ventures. Pendergast was formerly the president of human genetics therapies at Shire Pharmaceuticals, and before that was CEO of Cambridge, MA-based Transkaryotic Therapies. He’s now placing a big bet on a field of biology that isn’t being tapped by traditional pharmaceutical or biotech companies, and that’s still three to five years away from entering clinical trials, Pendergast says.

“We’re talking about restoring a natural function that works for people,” Pendergast says. “It has a lot of appeal, as opposed to a lot of other drugs that try to block something, and you may not always understand the unintended consequences of that.”

Some of the pioneering work in this field of biology comes from the lab of Proteostasis co-founder Andrew Dillin at the Salk Institute in San Diego. A series of experiments there and other labs have given the venture capitalists confidence that it’s time to invest, Pendergast says. The researchers were able to show they could stimulate the pathways that control protein homeostasis using conventional small-molecule drugs that are cheaper and easier to make than drugs produced through genetic engineering, he says. The effect is reversible, and reproducible in rodents, worms, and tissue cultures growing in lab dishes, he says.

It sounded to me like a technology that could potentially be applied as a preventive medicine. Who wouldn’t want a pill, for example, that might be able to ensure 70-year-olds will maintain order in the protein network responsible for clearing up amyloid plaques in the brain, which are thought to play a key role in Alzheimer’s disease?

It’s theoretically possible to do that, Pendergast says, but that’s not what the company has in mind. To get a drug approved by the FDA, the company would aim to treat patients who already have mild-to-moderate Alzheimer’s disease, then give them the drug for a six-month or one-year period, and use standard measures tracking their cognition. It would take many more years, and loads of more capital, to show, say, that healthy 70-year-olds who take a Proteostasis drug have a lower risk of getting Alzheimer’s by the time they turn 80.

That’s a pretty far-out, futuristic vision, and not really on the company’s agenda, Pendergast says. For now, Pendergast is focused on hiring a chief scientific officer and scientific team of 20 people over the next 12 to 18 months, to better understand the protein networks it is thinking about targeting.

It’s a new challenge for Pendergast, whose experience is with leading bigger companies. “Here, you’re starting with a blank sheet of paper,” he says. “It’s a building project. We’re excited, and we think this is an exciting area of biology, and we hope we can show significant benefit for patients.”

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