GOVERNMENT

NIH award to propel biomedical informatic, clinical, and animal studies

Researchers from Case Western Reserve University School of Medicine and collaborators have received a five-year, $2.8 million grant from the National Institute on Aging to identify FDA-approved medications that could be repurposed to treat Alzheimer's disease. The award enables the researchers to develop supercomputer algorithms that search existing drug databases, and to test the most promising drug candidates using patient electronic health records and Alzheimer's disease mouse models.

Rong Xu, PhD is principal investigator on the new award and associate professor of biomedical informatics in the department of population and quantitative health sciences at Case Western Reserve University School of Medicine. The project builds on Xu's work developing DrugPredict, a computer program that connects drug characteristics with information about how they may interact with human proteins in specific diseases--like Alzheimer's. The program has already helped researchers identify new indications for old drugs.

"We will use DrugPredict, but the scope of this project is much more ambitious," Xu said. Xu plans to develop new algorithms as well as apply DrugPredict to Alzheimer's, building a publicly available database of putative Alzheimer's drugs in the process. The database will include drugs that have potentially beneficial mechanisms of action and that are highly likely to cross the blood-brain barrier.

The blood-brain barrier has been a major obstacle in drug discovery for brain disorders, including Alzheimer's disease. The protective membrane surrounds the brain to keep out foreign objects--like microbes--but can also keep out beneficial drugs. "Finding drugs that can pass the blood-brain barrier is the 'holy grail' for neurological drug discovery," Xu said. "With this award, we will develop novel machine-learning and artificial intelligence algorithms to predict whether chemicals can pass the blood-brain barrier and whether they may be effective in treating Alzheimer's disease."

The research team includes XiaoFeng Zhu, PhD, professor of population and quantitative health sciences at Case Western Reserve University School of Medicine, and David Kaelber, MD, PhD, chief medical informatics officer at MetroHealth. Together, they will work with Xu's research group to validate repurposed candidate drugs with computer-simulated clinical trials, involving electronic health records from more than 53 million patients nationwide. Xu will also team up with co-principal investigator on the award Riquiang Yan, PhD, vice chair of neurosciences at Cleveland Clinic's Lerner Research Institute, to study the most promising drug candidates in mice genetically modified to have Alzheimer's-like disease.

The new award could lead to human studies testing alternative medications for Alzheimer's disease. "The unique and powerful strength of our project is our ability to seamlessly combine novel computational predictions, clinical corroboration, and experimental testing," Xu said. "This approach allows us to rapidly identify innovative drug candidates that may work in real-world Alzheimer's disease patients. We anticipate the findings could then be expeditiously translated into clinical trials."

Xu was invited to speak about the newly funded project at the National Institutes of Health Alzheimer's Research Summit this March. She will also serve as a panelist on Emerging Therapeutics at the conference.