The project tests the hypothesis that age-related RNA pollution accumulating in neurons, combined with predisposing genetic mutations, drives neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS, and aims to reverse neurodegeneration by eliminating this RNA pollution.

The goal is to slow age-dependent RNA dysregulation to confer resilience against neurodegeneration, potentially leading to new therapies that protect millions from these diseases.

The overarching hypothesis is that mitigating age-related RNA dysregulation can confer neuronal resilience even with pathogenic genetic variants, potentially shifting treatment toward proactive cellular rejuvenation.

Key personnel include co-principal investigators Douglas Galasko and Jerome Mertens, Alex Chaim, Fred “Rusty” Gage, and Anne Bang, spanning UC San Diego, Salk Institute, and Sanford Burnham Prebys.

Key collaborators, led by Gene Yeo at UC San Diego, include Galasko, Mertens, Chaim, Gage, and Bang, forming a cross-institution team.

Promising candidates will be tested in 3D brain tissue models called iSpheroids and later in animal models to evaluate potential effectiveness in humans.

Leading therapeutics will be evaluated in iSpheroid models that mimic brain tissue architecture, bridging cell culture and in vivo studies for efficacy and safety before advancing.

The project exemplifies state support for high-risk frontier science in regenerative medicine, aiming to alter the trajectory of chronic brain diseases through discovery and clinical research.

Robotics-enabled high-throughput screenings will identify thousands of potential treatments, including FDA-approved small molecules and targeted RNA therapies, that can reduce RNA pollution and restore neuronal health.

The screenings will assess thousands of compounds for their ability to clear RNA pollution and rejuvenate neuronal function, prioritizing candidates with translational potential due to prior safety data.

The collaboration among UC San Diego, Salk Institute, and Sanford Burnham Prebys has secured a four-year, $13 million CIRM grant to explore reversing age-related neurodegeneration by eliminating RNA pollution in aging neurons.

The project aligns with CIRM’s DISC4 portfolio, a broader $80 million commitment to six California researchers pursuing foundational science with translational potential in regenerative medicine.