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Dewpoint Debuts with $60M to Target Protein Droplets Linked to Disease

Xconomy Boston — 

An exciting new area of cell biology research that has emerged in only the last decade has already spawned a startup, which launches today with $60 million in Series A financing.

Dewpoint Therapeutics seeks to develop drugs that target a kind of liquid droplet widely found inside cells. These droplets (think bubbles of oil in water), called biomolecular condensates, contain proteins and RNA that group together as a way of organizing and compartmentalizing themselves in the cell. While this droplet formation, known technically as “liquid-liquid phase separation,” is involved in a variety of normal cellular activities, it’s also linked to diseases including cancer and neurodegeneration.

For decades, biologists have seen these membrane-less blobs in cells but didn’t know what they did. That’s changed in the last 10 years with a steady stream of studies, including many from one of Dewpoint’s scientific founders and a pioneer in the field, Anthony Hyman of the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany. He and other researchers have shown that these fluid-like blobs work by concentrating proteins and RNA at specific locations in the cell, which speeds up key chemical reactions inside the droplets, while keeping other molecules out to slow down or block other kinds of reactions.

The droplets can fuse together, break apart, and change their size, physical properties and composition—all thought to be regulated processes. And like most other things in the cell, when the regulation of condensates breaks down, disease can ensue.

These insights into phase separation have shifted how many biologists think about how the cell is organized, and are now also giving drug developers ideas for news ways of targeting proteins with drugs.

Amir Nashat, Dewpoint’s interim CEO and a managing partner at Polaris Partners, contrasts his company’s approach to traditional ways of drugging proteins, which generally involve blocking the production or activity of a disease protein. “What’s becoming clear from Tony’s work and from others is that it’s not just activity [of a protein],” Nashat says. “Location matters a lot too.” Being located inside a condensate, in close proximity to other key molecules, could be what turns a protein on, he says, and pulling it out of the blob could effectively shut it down.

Dewpoint is aiming to develop primarily small molecule drugs that can bind to previously unexplored regions of proteins to change how they behave when it comes to making these droplets. Depending on the disease, a drug might disrupt condensates, or cause them to form, or change their properties, says Mark Murcko, Dewpoint’s chief scientific officer. Murcko says this approach could be a new way of drugging known proteins. “We can go back to well-established targets that have been undruggable and look at them with fresh eyes,” Murcko says.

The startup will initially focus on neurodegenerative disease and cancer—two disease areas that have been linked to these condensates—but will also look at other disease areas, Murcko says. In neurodegeneration, researchers studying tau, a protein that clumps together into tangles in the brains of Alzheimer’s patients, have suggested that an early step in this clumping process could be that tau molecules, which start off as harmlessly soluble, come together into large liquid-like droplets that become gel-like. They then go on to trigger the formation of larger tau aggregates.

Tanja Mittag, a biologist at St. Jude Children’s Research Hospital in Memphis, TN who studies the role of phase separation in cancer and neurodegenerative disease and is not connected to Dewpoint, says it’s still early days for the field. “The details of how phase separation and neurodegeneration are linked are still unclear and whether it is a causative link needs to be tested,” she says. But she adds that the possibility of finding new therapeutics in this area is “exciting.”

Dewpoint is just beginning operations—the company founders decided only in September to start Dewpoint. Nashat says the new funding should last his company three years. Dewpoint has a long way to go; Nashat says by the end of those three years, his company will probably still be in preclinical drug development, rather than entering clinical trials. For now, he’s focused on hiring, in both Cambridge, MA, and in Dresden.

Polaris, Dewpoint’s founding investor, led the Series A round, and was joined by Samsara BioCapital, 6 Dimensions Capital, EcoR1 Capital, and Leaps by Bayer.