Backed by the combined expertise of three USC schools, scientists are developing a new drug aimed at a previously unexplored biological target in Alzheimer's disease, aided by an $8 million grant from the National Institutes of Health.
The team, led by Hussein Yassine of the Keck School of Medicine of USC, is investigating why some carriers of the APOE4 gene - the strongest genetic risk factor for Alzheimer's - develop dementia while others remain cognitively healthy.
"Our lab has identified an enzyme that predisposes the brain to inflammation," Yassine said. "The challenge now is to find a drug that can block it without harmful side effects."
Their work points to an enzyme which breaks down protective omega-3 fatty acids in the brain and triggers damaging inflammation.
Partners across the university
To tackle that challenge, Yassine partnered with Vsevolod "Seva" Katritch of the USC Dornsife College of Letters, Arts and Sciences and the USC Michelson Center for Convergent Bioscience. Katritch's lab is using a combination of artificial intelligence and physics-based tools to scan billions of small molecule candidates to find those that can penetrate the brain's protective barrier and fit into the enzyme's active site, like a key in a lock.
"We've developed computational tools that allow us to do it very fast," said Katritch, who uses a computational platform that he developed called V-SYNTHES. "This actually got us to pre-clinical candidates in less than two years."
The third arm of the collaboration is led by pharmacologist Stan Louie of the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences who is guiding the transition from laboratory discovery to a safe medication. He determines how the drug behaves in the body: how it's metabolized, how it's eliminated and whether the drug works as intended or poses potential risks. All are key steps before advancing testing to phase 1 clinical trials in people.
Kai Chen, a professor of research radiology at Keck School of Medicine, leads the team that is capturing images of the drug's impact on brain inflammation.
Alzheimer's disease affects about 6 million Americans and costs the U.S. economy an estimated $320 billion annually. Despite decades of research, the few approved drugs have only a modest impact on the amyloid plaques or tau tangles that are hallmarks of the disease. The USC researchers hope that targeting brain inflammation will offer a new therapeutic pathway.
The grant award, spread across five years, is a windfall for Yassine's project. He's been exploring the role of the enzyme known as "calcium-dependent phospholipase A2," or cPLA2, for about a decade. As his team studied differences in APOE4 gene carriers, they found that the ones with elevated levels of cPLA2 were the ones who developed dementia.
Yassine wondered why no one else had explored this pathway; after a deep dive into the scientific literature, he found out that cPLA2 belongs to a family of enzymes that look very similar.
"And drugs developed to date are not very selective, so if they can inhibit this enzyme, they might, at higher doses, inhibit the neighboring enzyme," Yassine said. "And the other enzymes are quite essential - so if you inhibit them, you're going to have problems, for sure."
Narrowing the field
With help from the Katritch Lab, Yassine has narrowed the field of possible drug formulations to target cPLA2 selectively. He's now on the third generation of possible candidates and homing in on one that would be good enough for a pharmaceutical company to take to clinical trials.
"Using support from NIH, we are translating these discoveries into a drug that can get into the clinic," Louie said. "Ultimately, we want to know if inhibiting inflammation can reduce the impact of Alzheimer's disease."
In recent work, Yassine's team found that when they blocked cPLA2 in models of Alzheimer's disease, they not only enhanced the beneficial action of omega-3 fatty acids in the brain but also repaired the blood-brain barrier. Other Alzheimer's studies have shown that leaky blood vessels in the brain slow down blood flow and let harmful substances leach into brain tissue.
If successful, the project could yield the first brain-penetrant, highly selective inhibitor of cPLA2, opening a new chapter in the treatment of neurodegenerative disease.
"It takes a team to turn discovery into hope," Yassine said.
