Engineering a Compact Epigenome Editor to Treat Fatal Prion Disease
Epigenome editing offers lasting gene repression without DNA damage. Editors like CRISPRoff confer durable, targeted transcriptional silencing through DNA methylation at gene promoters but have limited therapeutic potential due to toxicity and large transgene size. We solve this by developing CHARMs: compact, nontoxic effectors that enable epigenome editing in the CNS. We demonstrate robust silencing of the prion protein in mouse brains using AAV-mediated delivery of CHARMs, paving the way for treatment of fatal prion diseases.