Investigating inhibition of IDOL as a therapeutic target
The risk for developing Alzheimer’s disease is influenced by genetic variants in a small number of genes. Among these genes, apolipoprotein E (ApoE) variants are by far the strongest genetic risk factor for late-onset Alzheimer’s disease, the most common form of the disease.
In the brain, ApoE interacts with several receptors that are members of the low-density lipoprotein receptor (LDLR) family. ApoE, through interacting with its receptors, strongly influences the initiation and progression of the disease. Therefore, ApoE and its receptors are targets for the development of disease-modifying therapies for Alzheimer’s disease.
Dr. Gao’s previous research had identified a molecule, named the inducible degrader of the LDLR (IDOL), that regulates the level of brain ApoE receptors. Deletion of IDOL improves Alzheimer’s disease pathology in models, suggesting inhibition of IDOL may be a novel therapeutic target for Alzheimer’s disease.
Antisense oligonucleotides (ASOs) are short, synthetic, single-stranded oligodeoxynucleotides that can modify the level of select molecules. ASOs have been studied as potential drugs for diseases such as cancers, amyotrophic lateral sclerosis (ALS), and muscular dystrophy.
In their research, Dr. Gao and his team will test the effects of an ASO targeting brain IDOL in several models of Alzheimer’s disease. Preliminary research so far has shown promising results. With additional tests, ASO against IDOL has the potential to advance to human clinical trial as a novel therapy for Alzheimer’s disease.
They will test the ability of this ASO to slow the progression of Alzheimer’s disease, and it may also be used as preventive medications for patients who have a higher risk of developing Alzheimer’s disease.
“We hope to determine whether ASO targeting IDOL will slow down the progression of Alzheimer’s disease and improve the cognitive functions in animal models of Alzheimer’s disease,” Dr. Gao said. “If this proves true, then the outcome of this proposal would provide strong preclinical evidence to support clinical development of IDOL ASO.”
“I am thrilled about this award. It recognizes Dr. Gao’s scientific innovation and remarkable early successes in identifying IDOL, a protein involved in lipoprotein metabolism, as a new therapeutic target to treat Alzheimer’s disease,” says Phillip Popovich, PhD, professor and chair of Neuroscience. “Ironically, reducing this same protein, may also reduce cholesterol levels in the blood and decrease the risk of heart attacks. Dr. Gao is one of our brightest new faculty, and the Thome Foundation Award is recognition that his research program is at the cutting edge in the Alzheimer’s disease field.”
About Dr. Gao
Dr. Gao joined The Ohio State University College of Medicine’s Department of Neuroscience as assistant professor in November 2018. He has been working on Alzheimer’s disease since 2012 as a postdoctoral fellow at the University of California, Los Angeles, where he worked with Peter Tontonoz, MD, PhD. Alzheimer’s research has been Dr. Gao’s focus for the past five years.
He is a member of Alzheimer's Research Center of Excellence, an Alzheimer’s disease research community at Ohio State that is committed to better understanding the pathology and develop effective approaches for the treatment of Alzheimer’s disease.
In addition to the Thome Award, Dr. Gao received a Pathway to Independence Award (K99/R00) in 2017 from the NIH’s National Institute on Aging. This award advanced his academic career, allowing him to transition from a postdoctoral researcher to an independent investigator.