The Broad Institute has received a USD 11.3 million NIH U19 renewal to advance gene editing approaches aimed at permanently lowering prion protein (PrP) expression in the brain — a strategy that could yield the first disease-modifying therapy for prion disease, a uniformly fatal neurodegenerative condition with no approved treatments.
The award, funded through the NIH Office of the Director and administered by the National Institute of Neurological Disorders and Stroke, supports three parallel editing modalities: a dual-vector base editor, a single-vector base editor, and a single-vector epigenome editor. Each targets PRNP, the gene encoding PrP, with the goal of durably suppressing expression in the central nervous system following a single administration. The program will select a lead modality at the end of Year 2 based on head-to-head comparisons of potency, brain biodistribution, durability, and tolerability, with at least one backup approach continuing in parallel.
The scientific rationale is well-established. PrP is the obligate substrate for prion replication and neurotoxicity, yet loss-of-function variants appear benign in humans, and PrP knockout animals show no severe phenotype. Antisense oligonucleotide studies have provided pharmacologic proof-of-concept that PrP lowering is protective across prion strains and disease stages, but require repeated dosing. A gene-editing approach aims to make that suppression permanent.
Principal investigator Sonia Minikel Vallabh has been a central figure in prion disease research, bringing both scientific expertise and personal stake to the program. The consortium structure integrates prion biology, genome-editing tool development, and viral vector production, supported by shared animal models, pharmacodynamic biomarker assays, a patient registry, and a dedicated vector core.