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 out the links between the networks with bioinformatics, Licholai says. It’s also designing drug that won’t necessarily shut down, or completely block, the protein network activity, but rather will alter the pathways to make them more stable and preserve their healthy function, Licholai says.
Avid biotech readers will notice anytime you talk about diseases of aging that it sounds a lot like what Cambridge, MA-based Sirtris Pharmaceuticals has been pursuing for years. While Proteostasis doesn’t focus on the same exact targets, known as sirtuins, Licholai says there is some overlap between the companies because the sirtuins are elements of, and are related to, the protein networks that Proteostasis is focusing on.
Proteostasis’ lead program at the moment is being designed to treat Huntington’s disease, although it could be useful in a number of neurodegenerative diseases, Licholai says. It is being aimed at HSF1, a heat shock transcription factor. It’s a master switch regulator of a process cells undergo when they are under stress. This program climbed on the priority list after the study in C. elegans showed a “very dramatic” effect with a small molecule compound that doubled lifespan. The next step is to see if the finding can be confirmed in mice, Licholai says.
Heat shock proteins are familiar as cancer targets, and have long been subject of research and development at companies like Cambridge, MA-based Infinity Pharmaceuticals, Biogen Idec, and Hayward, CA-based Kosan Biosciences before that company was acquired by Bristol-Myers Squibb two years ago. One difference with Proteostasis is that it’s not focusing on cancer, Licholai says.
Other companies, like Cambridge, MA-based FoldRx Pharmaceuticals and Cranbury, NJ-based Amicus Therapeutics, are concentrating on how to stop proteins from causing diseases when they become misfolded. FoldRx is a close relative to Proteostasis, given that Scripps’ Kelly is one of the founders, and HealthCare Ventures invested.
What’s different at Proteostasis, Licholai says, is its focus on the entire network of proteins, and its insistence on marrying bioinformatics talent to map out the networks, along with a traditional drug discovery capability that comes from chemistry, biology, and pharmacology. “I don’t think anybody else is looking at it from a network biology point of view,” Licholai says.
Licholai is not a newbie in the field, he previously worked five years at Amicus, telling its story to doctors, business development pros, and investors. He said he’s seen protein folding and protein network biology rise from obscurity just five years ago, into the kind of thing that hundreds of labs around the world now pursue, and which draws conferences at places like Cold Spring Harbor Laboratory.
“How many times do you get a chance to catch the wave, in a new field of science?” Licholai says. “When I heard this company was being put together by HealthCare Ventures and Jeff Kelly, I thought that sounds great and I really want to get involved.”
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