Drug Development

Making Advances in Personalized Alzheimer’s Care

Developing a drug for Alzheimer’s disease is a fundamental goal of the USC Center for Personalized Brain Health. We pursue a dual approach to advancing Alzheimer’s treatment among carriers of the APOE ε4 gene variant, which magnifies the risk for the disease.

For those earlier in life, we focus on repairing a mechanism that is disturbed in APOE ε4 carriers: the body’s delivery and use of lipids such as fatty acids, believed to be vital to keeping the brain healthy.

For those later in life, we focus on excessive brain inflammation. Neuroinflammation is known to be a major cause of the degeneration seen in Alzheimer’s disease.

The Center for Personalized Brain Health launched its Alzheimer’s drug development pipeline with a compound that shows promise for achieving both of these objectives. In laboratory testing, the drug candidate, improved the processing of lipids and quieted brain inflammation.

Our translational enterprise will drive its analogs and other potential therapies forward from the lab to clinical trials in patients.

From Clue to Candidate

The protective role of omega-3 fatty acids in brain health led our team to investigate whether more omega-3s would help APOE ε4 carriers with Alzheimer’s disease. The perplexing answer was that increasing intake did not provide benefits. This suggested that there was an underlying mechanism that needed to be addressed.

Subsequent studies showed that APOE ε4 carriers accumulate more compounds in their bodies that break down omega-3s, compared to non-APOE ε4 carriers. The effect was even more pronounced in APOE ε4 carriers who had Alzheimer’s disease.

From there, we focused on an enzyme called cytosolic phospholipase A2 (cPLA2). Lab results suggested that cPLA2 was responsible for breaking down omega-3s for energy, rather than allowing them to support normal brain functions, such as memory formation. Crucially, inhibiting this enzyme in lab models increased the levels of omega-3 fatty acids in the brain and enhanced cognitive function.

Working with colleagues at the USC Michelson Center for Convergent Bioscience, our team searched for a molecule likely to be safe and effective in blocking the action of cPLA2. Using computer modeling to screen a database of more than 18 billion compounds, we found BRI-50054. Further laboratory research indicated that this small molecule lowers cPLA2 activity, increases the amount of omega-3 fatty acids in the brain, and inhibits neuroinflammation.

With BRI-50054 as our inaugural lead compound, the USC Center for Personalized Brain Health is establishing a robust enterprise for moving from biochemical clue to new Alzheimer’s treatment.