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In vivo base editing extends lifespan of a humanized mouse model of prion disease
Meirui An (Broad Institute, Howard Hughes Medical Institute), Jessie R. Davis (Broad Institute, Howard Hughes Medical Institute), Jonathan Ma Levy (Broad Institute, Howard Hughes Medical Institute), Fiona E. Serack (Broad Institute, Stanley Center for Psychiatric Research), John W. Harvey (Broad Institute, Stanley Center for Psychiatric Research), Pamela P. Brauer (Broad Institute, Stanley Center for Psychiatric Research), Catherine P. Pirtle (Broad Institute, Stanley Center for Psychiatric Research), Kiara N. Berríos (Broad Institute, Howard Hughes Medical Institute), Gregory A. Newby (Broad Institute, Howard Hughes Medical Institute), Wei-Hsi Yeh (Broad Institute, Howard Hughes Medical Institute), Nikita Kamath (Broad Institute, Stanley Center for Psychiatric Research), Meredith A Mortberg (Broad Institute, Stanley Center for Psychiatric Research), Yuan Lian (Broad Institute, Stanley Center for Psychiatric Research), Michael Howard (Broad Institute), Kendrick DeSouza-Lenz (Broad Institute), Kenia Guzman (Broad Institute), Aaron Thai (Broad Institute), Samantha Graffam (Broad Institute), Vanessa Laversenne (Broad Institute, Stanley Center for Psychiatric Research), Alissa A. Coffey (Broad Institute, Stanley Center for Psychiatric Research), Jeannine Frei (Broad Institute, Howard Hughes Medical Institute), Sarah E. Pierce (Broad Institute, Howard Hughes Medical Institute), Jiri Safar (Broad Institute, Stanley Center for Psychiatric Research), Benjamin E. Deverman (Broad Institute, Harvard University), Eric Vallabh Minikel (Broad Institute, Harvard University), Sonia M. Vallabh (Broad Institute, Howard Hughes Medical Institute), David R. Liu (Broad Institute, Howard Hughes Medical Institute)
Résumé : Prion disease is a fatal neurodegenerative disease caused by the misfolding of prion protein (PrP) encoded by the PRNP gene. While there is currently no cure for the disease, depleting PrP in the brain is an established strategy to prevent or stall templated misfolding of PrP. Here we developed in vivo cytosine and adenine base strategies delivered by adeno-associated viruses to permanently modify the PRNP locus to achieve PrP knockdown in the mouse brain. Systemic injection of dual-adeno-associated virus PHP.eB encoding BE3.9max and single guide RNA installing PRNP R37X resulted in 37% average installation of the desired edit, 50% reduction of PrP in the mouse brain and 52% extension of lifespan in transgenic human PRNP mice inoculated with pathogenic human prion isolates representing the most common sporadic and genetic subtypes of prion disease. We further engineered base editing systems to achieve improved in vivo potency and reduced base editor expression in nontargeting tissues, resulting in 63% average PrP reduction in the mouse brain from a 6.7-fold lower viral dose, with no detected off-target editing of anticipated clinical significance observed in either human cells or mouse tissues. These findings support the potential of in vivo base editing as one-time treatment for prion disease.