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understand what they do or their impact on brain function. Eventually, technologies such as genetically-engineered mice and the fluorescent chemical sensors invented by Nobel laureate Roger Tsien made possible the study of glial cells: astrocytes, oligodendrocytes, and microglia.
“[Microglia and astrocytes] have come in and out of favor the last 20 years,” says Irene Griswold-Penner, who as senior director of neurobiology at iPierian used models of glial cells and neurons—“brains in a dish”—to test the company’s antibody treatments for neurodegenerative diseases (now in the hands of Bristol-Myers Squibb).
“There would be some tiny bit of data that suggest a role for either some target in microglia or astrocytes in the neurodegenerative diseases, and then people just wouldn’t make headway.”
But there is now a growing body of scientific literature examining their role in brain function, and a greater understanding of the roles of the different types of glial cells.
Haydon made glial cells the focus of his research more than two decades ago, after a fluky experiment he ran in 1992 showed they released chemicals, rather than just being essentially inactive.
But the idea for his company came out of a lecture he attended in 2008. He heard someone say that if you stimulate a certain receptor on a microglial cell, it kickstarts phagocytosis. Think of that as the brain’s garbage men clearing out the trash around them by digesting it. Haydon surmised he could use a drug to do that in Alzheimer’s patients, since, he says, microglia cells surround beta-amyloid (the misfolded protein that forms plaques). But they don’t digest beta-amyloid correctly once the disease takes hold, perhaps because they are hampered by inflammation.
The drug is a small molecule that stimulates a receptor on microglia called P2Y6. Haydon says the drug appears to work in two ways: triggering phagocytosis and tamping down the release of an inflammatory cytokine, IL-12.
“The thinking is we’re taking the foot off the brake by removing inflammation, and at the same time we’re pushing our foot down on the gas to stimulate directly the clearance of amyloid beta,” Haydon says.
After early experiments in mice at Tufts that showed clearance of plaques Haydon developed some intellectual property and set up GliaCure in 2011 with the help of some “friends and previous business colleagues.” (He wouldn’t name them, only referring to his main benefactors as “wealthy individuals” who are “incredibly supportive of the program.”)
Other GliaCure officials are Rudy Schreiber, a former Evotec, Roche, and Sepracor executive, who is VP of translational research and development, and CFO Alan Barber, who is also president of financial management firm Prestar Group. GliaCure’s board includes Walter Dewey (a portfolio manager at Reinhart Partners), Michael Szulczewski (president of Prairie Technologies, acquired by Bruker in 2013) and Joe Zakrzewski (recently the CEO of Amarin).
Given just clearing out plaques on its own hasn’t been enough in clinical trials so far—high-profile antibody drugs like bapineuzumab and solanezumab did so, but didn’t improve patients’ lives—Haydon is hoping that two-pronged strategy will have different results.
Haydon claims his candidate, in an in vivo model, both reduced plaques and improved memory formation. He’s not aware of anyone else trying GliaCure’s specific approach on Alzheimer’s, but like any other untested mechanisms, it’s got its share of questions. For example, the drug disrupts the function of the P2Y6 receptor, which can be found on many other cells throughout the body, not just microglia.
“This receptor is one of the adenosine receptors, and pharmas have been trying to target the adenosine receptors for years,” says Griswold-Penner. “But you have to have such a clean inhibitor against the particular homologue that you’re interested in. You can have effects on the heart, all sorts of side effects, because there are so many adenosine receptors that affect every vital function in the body.”
Haydon notes specifically P2Y6’s presence on circulating T cells, a key component of the immune system. But his concerns have been allayed so far in animal studies, where the drug has proven “very safe” even after delivering a maximum dose—far higher than would be needed for a therapeutic response.
Then again, as Haydon acknowledges, “a [mouse] model is a model.”
Human studies are a different story. And potential side effects aside, even recruiting the right patients for those studies is a massive undertaking, because it’s still unclear when the right time is to treat an Alzheimer’s patient. Many drugs have been doomed by treating the disease too late in the process to make a real impact.
That’s yet another bridge GliaCure will have to cross eventually, and a major reason why the company plans to hedge its bets. It’ll test the drug’s anti-inflammatory/phagocytosis dual mechanism in other diseases like psoriasis and Parkinson’s, and plans to develop other glia cell-targeting candidates as fast-acting anti-depressants or sleep therapeutics as well.
To do that, however, GliaCure is going to have hire some full-timers and a CEO, raise a bunch of money, and presumably, move out of that condo.
“We are totally cognizant of the fact that it’s going to cost a lot of money, and we’ve got to find groups with deep pockets,” Haydon says. “The science is exciting. We’ve got to just make sure we can drive it forward.”