The National Institute on Aging (NIA), part of the National Institutes of Health, has awarded Dianne Perez, PhD, a five-year, $2 million grant to continue her work to develop a novel treatment for Alzheimer’s disease.
Dr. Perez, a staff member in the Department of Cardiovascular & Metabolic Sciences, has spent the last 30 years researching and developing a compound for cardiac ischemia that, in the last few years especially, has also shown great promise in improving cognition, learning and memory.
Despite having spent the majority of her career studying vascular diseases, she knew she could not overlook the cognitive benefits of the compound, which the team has come to informally call “compound 3.” The Alzheimer’s Drug Discovery Foundation (ADDF) and the Harrington Discovery Institute at University Hospitals together awarded Dr. Perez the ADDF-Harrington Scholar Award, which enabled her and her team to start testing compound 3 in preclinical models of Alzheimer’s disease.
The results of their investigations have been promising, Dr. Perez says, but this next phase of study, made possible by the support from NIA, will allow the team to further refine compound 3 and perform more dose and efficacy testing.
“We want to enhance some of compound 3’s chemical properties to increase its brain penetrance—or how much of the drug is able to effectively cross the blood-brain barrier,” she explained. “We also want to test the drug’s effectiveness, including at difference doses, in a more diverse model of Alzheimer’s disease.”
The pathology of Alzheimer’s disease is notoriously heterogeneous; it is one of the leading reasons an effective treatment has remained elusive. To date, Dr. Perez’s preclinical studies have made use of amyloid-based models. While plaques of beta-amyloid proteins are a hallmark feature of Alzheimer’s brains, there are other important brain changes seen in patients that should be reflected in preclinical models. Dr. Perez says that using different disease models will help broaden how their findings can be interpreted.
Compound 3: the basics and benefits to date
Dr. Perez’s original research focused on understanding the structure and function of a class of molecules called G-protein coupled receptors—specifically a type called α1-adrenergic receptors, which bind to the neurotransmitter norepinephrine and the neurohormone epinephrine. Epinephrine causes blood vessels to narrow, which increases blood pressure and adapts the heart to withstand damage, making it a viable treatment strategy for ischemia (where reduced blood flow causes a shortage of oxygen to the heart). For this reason, she set out to develop a drug that could imitate and amplify norepinephrine/epinephrine-receptor binding (these types of drugs are called agonists).
There are several subtypes of α1-adrenergic receptors. Dr. Perez discovered that overexpressing α1A receptors had profound cardio- and neuroprotective effects. Preclinical models with increased receptors of this type had reduced risk of ischemia and cancer, lived 10-15% longer and showed signs of improved cognition. They exhibited enhanced learning and memory, as well as increased neurogenesis and synaptic plasticity (formation of new neurons and connections between neurons).
“This is where we saw a real potential for an α1A agonist as a potential Alzheimer’s treatment,” Dr. Perez said. “But the problem was that α1A agonists have been shown to have harmful effects on blood pressure. If we were going to pursue this as a therapeutic approach for Alzheimer’s disease, we knew we needed to find a way to maintain the cognitive benefits without inadvertently raising blood pressure.”
The solution, Dr. Perez found, was to design compound 3 to be an agonist-like compound. Compound 3 still binds norepinephrine and epinephrine to α1-adrenergic receptors, but at a different site than normal.
So far, Dr. Perez has seen positive results from this chemical sleight of hand. Although compound 3 has taken on new life—pivoting from being used to potentially treat cardiac ischemia to now Alzheimer’s disease—Dr. Perez credits this success to the decades she has spent studying α1-adrenergic receptors and her background in chemistry. She received her PhD in chemistry from the California Institute of Technology.
In her most recent preclinical study, which was supported by the BrightFocus Foundation and the ADDF-Harrington Scholar Award, Dr. Perez and her team found that compound 3 significantly increased long term potentiation—an indicator of how strong the brain’s neuronal synapses in memory formation are—and cognitive behavior in models of Alzheimer’s disease without blood pressure changes.
“This phase of drug development can be difficult and expensive, and projects with early momentum often stall without external support,” said Dr. Perez, “so we are very excited to continue our work with this support from NIA. There are millions of Americans living with Alzheimer’s and we want to help bring them and their families an effective treatment. More research will be necessary, but we are eager at this phase to optimize compound 3 to the best of our ability.”
Future studies to refine compound 3’s properties will be done in collaboration with Shaun Stauffer, PhD, who directs Cleveland Clinic’s Center for Therapeutics Discovery and whose expertise in medicinal chemistry will help with drug optimization.
Photo credit: Harrington Discovery Institute