Pharmacy researcher develops intervention for metabolic diseases like diabetes, stroke and heart disease

An investigator with the University of Kansas School of Pharmacy has filed an invention disclosure, part of a provisional patent application with the United States Patent and Trademark Office, for a treatment that could apply to heart disease, stroke and a host of other human diseases related to metabolism.

Liqin Zhao, KU associate professor of pharmacology & toxicology and investigator at the Life Span Institute, has researched the human ApoE gene for years. A major focus of her work centers on how the ApoE2 variant—one of three major isoforms of ApoE gene— might protect people from Alzheimer's disease.

Now, based upon a discovery made during her Alzheimer's-disease work, Zhao is patenting a way to leverage rhApoE2 to regulate blood lipids. Lipids, like fats and oils, are building materials of life at the cellular level that also are tied to heart disease and other metabolic diseases.

"In essence, we found that rhApoE2 significantly lowered blood levels of a number of ceramides," Zhao said. "Moreover, rhApoE2 increased blood levels of a variety of 'good triglycerides'—triglycerides that contain health-promoting, long-chain polyunsaturated fatty acids such as alpha-linolenic acid, EPA and DHA, and lowered levels of 'bad triglycerides,' or triglycerides that contain saturated or monosaturated fatty acids that can impose a cardiovascular risk."

More and more, ceramide levels in the blood are seen by medical researchers and clinicians as a promising predictor of heart disease, perhaps a more useful metric than cholesterol readings. For example, the Mayo Clinic recently started using a blood test to quantify plasma ceramides as a new biomarker of cardiovascular risk prediction.

During a two-month experiment, Zhao and her team treated mice genetically altered to have aged vascular and neurological symptoms. They treated mice intravenously with rhApoE2, collected serum samples and then blindly evaluated them with a lipidomics analysis using advanced mass-spectrometry.

"The results were completely unexpected," Zhao said. "The lipidomics study was meant to determine whether a two-month intravenous exposure to rhApoE2 would cause any type of lipid dyshomeostasis (disruption of biological balance). We were pleasantly surprised to see that rhApoE2 not only did not induce a hyperlipidemic risk profile, but the treatment significantly improved the circulating lipidome of aged ApoE4 mice."

Zhao said the effect of rhApoE2 is unique, surpassing treatments available currently to patients at risk of heart disease.

"Currently no drugs have the capacity to systematically alter the circulating lipidome like what rhApoE2 has shown us," she said. "It's very exciting to envision that rhApoE2 may have the potential to fundamentally transform the treatment of metabolic diseases. In future studies, we'll need to address what might be the underlying biological basis that led to these effects from rhApoE2. It's probable that unknown factors, in addition to low-density lipoprotein receptors, may be involved in the dynamic regulation of the metabolism of those lipid classes."

The promise of ApoE2 as a treatment for human health goes beyond regulating levels of lipids in the blood. Zhao and her team filed a separate provisional patent application last November based on use of rhApoE2 to prevent and treat Alzheimer's disease.

"Over the last several years, we've learned a lot about ApoE2," the KU researcher said. "As a relatively rare variant, ApoE2 is an extraordinary protein with extraordinary properties. Our hope is that we can identify and translate some of the health benefits ApoE2 can provide into therapeutics for treating human diseases. I think we are in a great place towards accomplishing this goal."

Provided by University of Kansas