Just before the financial crisis hit in September 2008, Cambridge, MA-based Proteostasis Therapeutics was fortunate to snag $45 million of initial venture financing to pursue a dream. It has been pretty quiet since then. But behind the scenes, the idea has morphed into a company built to make convenient oral pills for diseases of aging.
Proteostasis was started by a big-name investor syndicate led by HealthCare Ventures. The founding science came from the San Diego labs of Jeffery Kelly at The Scripps Research Institute and Andrew Dillin at the Salk Institute for Biological Studies, and Richard Morimoto at Northwestern University. The money, and the brainpower, was supposed to rally around emerging biology that seeks to alter protein pathways that break down as people age, and lead to neurodegenerative diseases like Alzheimer’s and Parkinson’s.
“The philosophy was let’s take the leading lights in the academic field, who are defining and pushing this understanding of protein stability, and work with them and create a first-in-class, best-in-class company that is able to OWN this space. That’s the idea that went into Proteostasis, and that investors were sold on,” says Greg Licholai, the company’s chief operating officer.
The first six months or so were really nascent days, in which Proteostasis sought to precisely define goals and strategy, Licholai says. The company spent 2009 in the building phase—obtaining licenses to key intellectual property, hiring a team of 30 biologists, chemists, pharmacologists, and bioinformatics specialists. The big-name CEO from the beginning, David Pendergast, left, and chairman Chris Mirabelli of Healthcare Ventures now holds the title of interim CEO.
As the year went on, Proteostasis offered up some glimpses of its science. One paper in Nature Chemical Biology suggested an oral pill could restore partial function to lung cells from patients with cystic fibrosis. Another publication in the journal Cell showed how a pill might be able to stop the cumulative piling up of beta amyloid proteins that is thought to contribute to Alzheimer’s. A third study that Licholai told me about found that by altering a certain protein pathway in worms with Huntington’s disease, researchers could double their lifespan.
All of this research still has an extremely long way to go before it can reach a clinical trial, and Licholai didn’t want to divulge the company’s timetable for reaching that milestone. Still, the idea of altering not just one protein, but networks of proteins with convenient, oral small molecules is starting to attract attention from potential partners in the biotech and pharmaceutical industry, Licholai says.
The science of what’s happening here isn’t easy to explain in lay terms, but I’ll give it a whirl. The central dogma of biology says that DNA provides the instructional code for RNA, which makes proteins that carry out the functions in the body. Proteostasis sees itself navigating the complex intermediary steps in which the sequence for a protein is produced, but the protein still needs to pass through certain pathways to become fully functional, stable, and find its appropriate location in the cell. Sometimes these pathways degrade as we age and cause neurodegenerative diseases like Alzheimer’s, Parkinson’s, or Huntington’s. Or, the cumulative effect of high blood sugar puts stress on protein pathways, which perturbs the network, and leads to an altered state in which people develop insulin resistance and get diabetes, Licholai says. Scientists are only beginning to map out connections between these networks, and the trick will be to find the most important nodes on the network, Licholai says.
“Just like on the Internet, certain nodes have higher levels of connectivity than other nodes. Why is that important? Not all nodes are created equal. If Amazon.com loses its connectivity, that has a major effect on the network. The same thing is true from a biological point of view,” Licholai says. “Those are the ones to understand from a disease point of view, and from a drug discovery point of view.”
Anytime you start aiming a drug at a new target, especially one that’s an important crossroad for a lot of biological function, it’s obvious that a ton of work will need to be done to demonstrate this is safe. So Proteostasis is spending a lot of effort mapping
