Zinc Finger Repressors mediate widespread PRNP lowering in the nonhuman primate brain and profoundly extend survival in prion disease mice
Year: 2025
Type: preprint
Abstract: Prion disease is a rapidly progressing and invariably fatal neurodegenerative disorder with no approved treatment. The disease is caused by the self-templated misfolding of the prion protein (PrP) into toxic species, ultimately leading to neurodegeneration and death. We evaluated a novel epigenetic regulation approach using Zinc Finger Repressors (ZFRs) to ablate PrP expression at the transcriptional level. When delivered using adeno-associated virus (AAV), ZFRs potently and specifically reduced prion mRNA expression by >95% in vitro and to near undetectable levels within single neurons in vivo . In wildtype mice, ZFRs stably lowered neuronal PrP expression throughout the central nervous system for at least 17 months. In mice inoculated with misfolded PrP, AAV-ZFRs given at either early or late disease stages profoundly extended lifespan, significantly reduced PrP in the brain, and improved an array of molecular, histological, biomarker, and behavioral readouts. Finally, we delivered a ZFR targeting the human prion gene ( PRNP) to cynomolgus monkeys using a novel blood-brain-barrier penetrant AAV capsid. Extensive bulk and single-cell assessments revealed widespread ZFR expression and PRNP repression in all 35 brain regions assessed, providing the first demonstration of epigenetic regulation across the nonhuman primate neuraxis following a single intravenous (IV) dose. These results highlight the potential of a one-time IV administered ZFR treatment for prion disease and other neurological disorders.
Authors: Shih-Wei Chou, Meredith A Mortberg, Kimberly Marlen, David S Ojala, Toufan Parman, Michael Howard, Kendrick DeSouza-Lenz, Yuan Lian, Mohadeseh Mehrabian, Matthew Tiffany, Annemarie Ledeboer, Patrick Dunn, Jing Hu, Kenia Guzman, Nikita Kamath, Morgan Cass, Samantha Graffam, Leo M H Xu, Vanessa Laversenne, Taylor L Corridon, Alaric Falcon, Garrett Lew, Satria Sajuthi, Lei Zhang, Giulia Cisbani, Finn Peters, Tim Fieblinger, Chiara Melis, Janica Barenberg, Marharyta Hnatiuk, Qi Yu, Daniel Chung, Mihika Jalan, Sarah Hinkley, Yanmei Lu, Kathleen Meyer, Alissa A Coffey, Amy M Pooler, Sonia M Vallabh, Eric Vallabh Minikel, Bryan Zeitler
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4408280578