Researcher Narrows in on Novel Treatment for Alzheimer’s Disease

“Our laboratory motto for this project is ‘for the many and the few,’"

A University of Arizona College of Pharmacy scientist has received $3.8 million in federal funding to continue research to develop medications to help prevent or reverse the progression of Alzheimer’s disease.

Chris Hulme, PhD, professor of medicinal chemistry and a member of the college’s Arizona Center for Drug Discovery and the UArizona BIO5 Institute, is principal investigator for the five-year grant from the National Institute on Aging (NIA), part of the National Institutes of Health (NIH). He has been studying Alzheimer’s disease since 2012.

With no known cure, Alzheimer’s disease affects more than 5.5 million people in the United States. The number of people living with the disease, the most common cause of dementia beyond age 65, doubles every five years, according to the U.S. Centers for Disease Control and Prevention. Estimates indicate the disorder ranks third, behind heart disease and cancer, as a cause of death in older adults.

The NIA/NIH grant allows Dr. Hulme and a team of researchers at the UArizona Health Sciences to continue to develop a treatment to inhibit the activity of certain enzymes in Alzheimer’s patients. One such enzyme is DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase-1A), which plays a critical role in the development of neruological pathways in the brain and central nervous system. The enzyme has become an attractive drug target for researchers due to increasing evidence suggesting its overactivity may cause alterations to the brain of Alzheimer’s patients.

“To date, most Alzheimer’s treatments have focused on addressing only one disease symptom at a time, the most common being the appearance of amyloid plaques, proteins that accumulate in the spaces between nerve cells, which, in a healthy brain, normally are broken down and eliminated,” Dr. Hulme said. “However, our unique approach provides an opportunity to intervene in several areas simultaneously by inhibiting the activity of the DYRK1A enzyme.”

Dr. Hulme’s preliminary tests already have shown that blocking DYRK1A causes significant reductions in the decline of cognitive function and the development of the disease.

The DYRK1A gene also is located within chromosome 21, the region in a human cell that results in Down syndrome, when three copies are produced, as opposed to the usual two. Most individuals with Down syndrome show early-onset symptoms of Alzheimer’s, and the overexpression of DYRK1A is thought to be a significant contributor to this condition. Studies of Down syndrome in several animal models already have demonstrated the promise that DYRK1A-inhibition improves cognition.

“More than 150,000 Arizonans are living with Alzheimer’s disease, affecting individuals and families. Improving the health and happiness for our later years is a strategic priority for the University of Arizona, and we have a strong foundation for research for understanding Alzheimer’s disease,” said UArizona President Robert C. Robbins, MD. “Dr. Hulme and team are helping address a critical health-care challenge for our community by conducting vital research to develop innovative pharmaceutical interventions to prevent and potentially reverse this devastating disease and I look forward to seeing the results of his critical work.”

Dr. Hulme noted the team is not daunted by the challenge.

“Our laboratory motto for this project is ‘for the many and the few,’” he said. “By 2050, estimates predict 45 million cases of Alzheimer’s disease worldwide, yet we are loath to forget about lower-incidence diseases that are equally devastating for patients and their family members, such as Down syndrome.”

Dr. Hulme’s preliminary studies have demonstrated the feasibility of this approach and the recent discovery of an advanced lead, a compound known as DYR533, with former graduate student Dr. Christopher Foley, puts the project well positioned for possible clinical entry. With this funding, the team will seek to develop an orally bio-available theraputic that has the potential to both prevent and reverse the disease in advanced-stage Alzheimer’s patients.

Other investigators on this NIA grant include: Travis Dunckley, PhD, assistant research professor with the ASU-Banner Neurodegnerative Disease Research Center at the Arizona State University Biodesign Institute, and Bill Montfort, PhD, professor in the UArizona Department of Chemistry and Biochemistry and a member of the BIO5 Institute.

Research reported in this publication was supported by funding from the National Institute on Aging, a unit of the National Institutes of Health, under Award No. R01AG067926.