Base editing cuts PRNP 50% extends mouse life 52%
- Broad Institute researchers reported on January 14, 2025 that in vivo base editing of PRNP lowered prion protein in mouse brain and extended survival. (nature.com) - The key result was a 52% lifespan extension after a one-letter PRNP edit, with 50% lower brain PrP in infected humanized mice. (nature.com) - Next steps include follow-up preclinical work; a separate Ionis prion-lowering trial, ION717 PrProfile, lists estimated primary completion in February 2027. (clinicaltrials.gov)
Meirui An, Jessie R. Davis and colleagues reported on January 14, 2025 that an in vivo base-editing treatment aimed at the PRNP gene cut prion protein in mouse brain by about half and extended median survival in a prion-disease model by 52%. (nature.com) The paper, published in *Nature Medicine*, described a one-letter DNA edit delivered with dual adeno-associated viruses in transgenic mice carrying human PRNP and inoculated with human prion isolates. The target in the study was PRNP, the gene that encodes prion protein, or PrP. In prion disease, misfolded PrP drives a fatal neurodegenerative process that includes Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease and fatal familial insomnia, the paper said. (clinicaltrials.gov) The authors wrote that lowering PrP in the brain is an established strategy to prevent or slow the templated misfolding process, and noted that no approved therapies are available. The editing system used cytosine and adenine base editors packaged in AAV-PHP.eB vectors, according to the paper. The initial construct installed a PRNP R37X stop-codon edit, which the authors said produced an average 37% on-target edit rate, a 50% reduction of PrP in mouse brain and the 52% lifespan gain in infected animals. (nature.com) In a later optimized version, the team reported 63% average PrP reduction at a 6.7-fold lower viral dose, with no off-target editing of “anticipated clinical significance” detected in the human cells or mouse tissues they examined. David Liu, Sonia Vallabh and Eric Minikel were senior authors on the work, according to the paper and the Broad Institute. (nature.com) Broad said the study was the first demonstration that lowering prion protein improved lifespan in animals infected with a human version of the protein. Vallabh and Minikel, who both carry a pathogenic PRNP mutation and run a prion-disease lab at the Broad, have been central figures in efforts to develop PrP-lowering therapies. The mouse data do not amount to a human treatment. The study used a humanized mouse model, viral delivery into animals, and survival after inoculation with human prion isolates as the main efficacy readout. (nature.com) The paper described the findings as support for the “potential” of a one-time treatment, but it did not report results in human patients. A separate prion-lowering approach is already in the clinic. ClinicalTrials.gov lists Ionis Pharmaceuticals’ ION717 study, called PrProfile, as a Phase 1/2a trial evaluating intrathecal dosing in patients with prion disease. The registry lists an actual start date of January 4, 2024, estimated enrollment of 76 participants, estimated primary completion in February 2027 and estimated study completion in June 2030. (nature.com) Ionis describes ION717 as an investigational RNA-targeted medicine designed to inhibit production of prion protein. January 14, 2025 is the publication date attached to the base-editing paper, and the next concrete milestones are preclinical follow-up on the gene-editing approach and the ongoing ION717 clinical study. (nature.com) The *Nature Medicine* paper is indexed under DOI 10.1038/s41591-024-03466-w and PubMed ID 39810005, while the clinical trial is listed as NCT06153966 with primary completion estimated for February 2027. (broadinstitute.org) (clinicaltrials.gov)
