Researchers at the University of California, San Diego School of Medicine, the Salk Institute, and Sanford Burnham Prebys have received a four-year, $13 million award from the California Institute for Regenerative Medicine (CIRM) to study ways to reverse age-related neurodegeneration by eliminating what the researchers call the “RNA contamination” of aging neurons. The ultimate goal is to develop new treatments to protect against neurodegenerative diseases.
As brain cells age, they make more mistakes when processing genetic instructions (RNA). This creates RNA contamination that can accumulate over decades, stressing cells and making the brain highly vulnerable to diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), said lead researcher Dr. Gene Yeo, professor of cellular and molecular medicine at the University of California San Diego School of Medicine and director of the Center for RNA Technology and Therapeutics.
“Our working model is that if you have a genetic mutation that predisposes you to neurodegeneration, the mutation alone is not sufficient until age-related RNA contamination occurs,” said Yeo, who is also director of the Sanford Stem Cell Institute Innovation Center. “These combinations cause age-dependent diseases.”
The research initiative will investigate the root causes of cellular aging, rather than focusing on the terminal symptoms of neurodegenerative diseases, such as protein clumps in the brain. To do so, the research team is moving away from traditional animal models and standard stem cell methods, which often fail to reproduce human aging.
Typically, when scientists use a patient’s skin cells to create stem cells for brain research, the process “rejuvenates” the cells, erasing their biological age and accumulated RNA contamination. But in this study, the researchers use a technique called transdifferentiation to directly convert patients’ skin cells into what are called induced neurons (iNs). These cells retain the age of the original patient, making it possible to study how RNA contamination is formed.
The research team will then map signs of RNA contamination across more than 200 cell lines and patients’ biological fluids, such as spinal fluid and plasma, to understand how damage differs between healthy aging brains and brains suffering from neurodegenerative diseases. They will also investigate how disruption of cellular energy production by mitochondria contributes to the accumulation of RNA contamination.
Researchers will use advanced robotics to screen thousands of potential treatments that can remove RNA contamination and return neurons to a healthy state. This includes small molecule drugs and targeted RNA therapies already approved by the FDA for other conditions.
The most promising therapeutic candidates will be tested in iSpheroids, advanced 3D models of human brain tissue, and eventually in animal models to confirm that the treatments are likely to work in human patients.
“We hypothesize that if we can delay age-dependent RNA dysregulation, neurons will remain resilient to mutations that trigger neurodegeneration because they maintain their youthful resilience, even in the presence of mutations that trigger them,” Dr. Yeo said.
CIRM is a state agency that supports the development of innovative stem cell and gene therapies for a variety of diseases. “Reversing age-dependent neurodegeneration by removing RNA contamination” is one of six CIRM Discovery (DISC4) awards awarded to California researchers, with funding totaling $80 million approved.
This bold research initiative embodies UC San Diego’s commitment to advancing the frontiers of medicine and translating fundamental discoveries into tangible health solutions for some of the most challenging diseases we face today. At a time when federal research funding is uncertain, CIRM’s government-backed investments are essential to sustaining high-risk, high-impact research that will lead to the next generation of innovative treatments that protect millions of people from devastating neurodegenerative diseases. ”
John M. Carethers, MD, Vice President for Health Sciences
Co-principal investigators of this study include Douglas Glasco, MD, PhD, resident professor at UC San Diego School of Medicine, Jerome Mertens, PhD, associate professor in the Department of Neuroscience, and Alex Chaim, PhD, assistant professor in UC San Diego’s Department of Cell and Developmental Biology. Dr. Fred “Rusty” Gage, Professor in the Genetics Laboratory at the Salk Institute. Dr. Anne Bang, associate professor in Sanford Burnham Prebys Center for Therapeutic Discovery;
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University of California San Diego
