Alzheimer’s disease is a devastating condition that affects 6 million Americans and ranks as the sixth leading cause of death in the nation. It severely impairs patients’ quality of life and has no effective cure. With the aging of the population, the number of Alzheimer’s disease patients is expected to triple by 2060, according to the Centers for Disease Control and Prevention, creating an urgent medical need for novel treatments.
A protein called soluble epoxide hydrolase (sEH) could be key for treating Alzheimer’s disease, as it is found at higher levels in patients with this condition. Inhibition of the sEH protein may prove useful in treating the neuro-degenerative disease.
However, Kin Sing Stephen Lee, Ph.D., assistant professor at the MSU College of Osteopathic Medicine in the Departments of Pharmacology and Toxicology, and Chemistry, said “although sEH inhibitor (sEHI) molecules have demonstrated high potency, they share the common problem of poor predicted blood-brain barrier penetration.” This means they cannot reach the brain effectively, which is essential for producing a significant response.
Dr. Lee believes that he has found a way to improve sEHI blood-brain barrier penetration, and was recently awarded a $3.1 million grant from the National Institutes on Aging to further pursue his research.
Preliminary studies for the project were supported by the MSU Molecular Discovery Grant program and the ADVANCE Grant Program (ADVANCE is funded by the Michigan Strategic Fund and administered by the Michigan Economic Development Cooperation), leveraging expertise at MSU to create a team to develop therapeutic candidates for future preclinical testing. The team, headed by Dr. Lee, also includes Edmund Ellsworth, Ph.D., Anne Dorrance, Ph.D., and Teresa R. Krieger-Burke, D.V.M., Ph.D., from the MSU Department of Pharmacology and Toxicology, Scott Counts, Ph.D., and Nicholas Kanaan, Ph.D., from the MSU Department of Translational Neuroscience, Alex Dickson, Ph.D., from the MSU Department of Biochemistry and Molecular Biology, and Ma Wenjuan, Ph.D., from the MSU Center of Statistical Training and Consulting.
The team will investigate how various structural modifications to sEHI’s can affect their ability to cross the blood-brain barrier and increase central nervous system (CNS) exposure.
“We will apply a novel design-test-learn strategy to guide the design of the novel sEHIs using our in-house assays to screen sEHIs potency, binding kinetics and in vitro pharmacokinetic parameters,” Dr. Lee explained. “The top candidates will then be screened for their in vivo pharmacokinetic properties and CNS exposure.”
The team will fine-tune the most promising sEHI modifications to further enhance their drug-like properties and their ability to reach the brain. They will select the best sEHIs that can block at least 90% of brain sEH with a low dose and test them in animal models of Alzheimer’s disease to evaluate their effectiveness.
Current treatments for Alzheimer’s disease are only marginally effective. “They may slow down the disease progression but cannot stop or reverse the damage,” Dr. Lee said. The new sEHI technology could offer better outcomes for patients and lower costs. “We urgently need better treatments because this is a chronic disease and patients will likely need to take medications for their entire lives, creating a huge economic burden for themselves, their families and society.”
Dr. Lee is optimistic about this approach and hopes that if it works for Alzheimer’s disease, it can also pave the way for developing diagnostic tools and treatments for other neuro-degenerative diseases, such as Parkinson’s disease.