Scientists seek to reverse neurodegeneration by eliminating harmful RNA pollution

Researchers at 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 investigate how to reverse age-related neurodegeneration by eliminating what the researchers call "RNA pollution" in aging neurons. The ultimate goal is to develop new therapies to protect against neurodegenerative diseases.

As brain cells age, they often make mistakes when processing their genetic instructions (RNA). This creates RNA pollution, which accumulates over decades, stressing the cells and making the brain highly vulnerable to diseases like Alzheimer's, Parkinson's and Amyotrophic Lateral Sclerosis (ALS), according to principal investigator Gene Yeo, PhD, professor of cellular and molecular medicine at UC San Diego School of Medicine and director of the Center for RNA Technologies and Therapeutics.

"If you have a pre-disposing genetic mutation for neurodegeneration, our working model is that the mutation by itself does not suffice until you have this age related-RNA pollution," said Yeo, who is also director of the Innovation Center at the Sanford Stem Cell Institute. "The combination results in age-dependent disease."

Instead of focusing on the late-stage symptoms of neurodegenerative diseases, like protein clumps in the brain, the research initiative will investigate the root causes of cellular aging. To do so, the team is moving away from traditional animal models and standard stem cell methods, which often fail to replicate human aging.

Normally, when scientists use skin cells from patients to create stem cells for brain research, the process "rejuvenates" the cells, erasing their biological age and any accumulated RNA pollution. In this study, however, the researchers will use a technique called transdifferentiation to convert patient skin cells directly into what they call induced neurons (iNs). These cells retain the age of the patients they came from, making it possible to study how RNA pollution forms.

The team will then map out signatures of RNA pollution across more than 200 cell lines and patient biofluids like spinal fluid and blood plasma to understand how the damage differs between healthy aging brains and those with neurodegenerative diseases. They will also investigate how a breakdown in the production of cellular energy by mitochondria contributes to the buildup of RNA pollution.

Using advanced robotics, the researchers will conduct screenings of thousands of potential treatments that can clean up the RNA pollution and restore neurons to a healthy state, including small-molecule drugs that have already been approved by the FDA for other conditions and targeted RNA therapies.

The most promising therapeutic candidates will be tested on "iSpheroids", advanced 3D models of human brain tissue, and eventually in animal models to ensure the therapies have a high chance of working in human patients.

"We hypothesize that if we can slow down the age-dependent dysregulation of RNA, even if you have a mutation that is a trigger for neurodegeneration, you will still be resilient to it because your neurons will maintain a youthful resilience," said Yeo.

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 elimination of RNA pollution" is one of six CIRM Discovery (DISC4) awards to California researchers that have been approved for a combined total of $80M in funding.

This bold research initiative embodies UC San Diego's commitment to advancing the frontier of medical science and translating fundamental discoveries into tangible health solutions for some of the most challenging diseases we face today. In a time of uncertain federal research funding, CIRM's state‑backed investment is indispensable, sustaining the high‑risk, high‑impact work that will usher in the next generation of innovative therapies that will protect millions from devastating neurodegenerative diseases."

John M. Carethers, MD, Vice Chancellor for Health Sciences

Co-principal investigators on the study include Douglas Galasko, MD, professor in residence and Jerome Mertens, PhD, associate professor in the Department of Neurosciences at UC San Diego School of Medicine, and Alex Chaim, PhD, assistant professor Department of Cell and Developmental Biology at UC San Diego; Fred "Rusty" Gage, PhD, professor in the Laboratory of Genetics at the Salk Institute; and Anne Bang, PhD, associate professor in the Center for Therapeutics Discovery at Sanford Burnham Prebys.