Therapeutic Editing to Lower PrP in Prion Disease

Prion disease is a fatal, untreatable neurodegenerative disease caused by the prion protein (PrP). Encoded by the chromosomal gene PRNP and expressed ubiquitously in all mammals, PrP is not pathogenic in its native state, but causes disease when it misfolds into a "prion" capable of conformationally corrupting other PrP molecules. PrP is the obligate substrate in all disease forms and subtypes, and is absolutely required for both prion replication and prion neurotoxicity. PrP is, however, dispensable for healthy life, with no severe knockout phenotype in mice, cows, or goats, and no evidence that loss-of-function variants are harmful in humans. Decades of genetic proofs-of-concept, bolstered by recent pharmacologic proofs-of-concept from antisense oligonucleotides, argue that PrP lowering is dose-dependently protective against prion disease, across strains and across a spectrum of disease stages. Accordingly, our program will be oriented around the goal of advancing a permanent, one-time PrP-lowering gene therapy for human use. To drive towards this goal we have assembled a team that unites expertise across the following complementary and synergistic domains: prion disease biology, development and optimization of genome-editing tools, and viral vector development and production. Our program will be structured around three lightly connected Research Projects, each of which will optimize and explore one of the following distinct editing modalities for its ability to lower PrP levels in the brain: 1) a dual vector base editor; 2) a single vector base editor 3) a single vector epigenome editor. These projects are united by their shared therapeutic goal, but selected to diversify risk across the project portfolio and to enable mutual acceleration through shared learnings. The structure of the program will allow all three approaches to benefit from access to shared models and resources including faithful animal models of prion disease, pharmacodynamic biomarker assays, genetic and natural history datasets, shared clinical trial design considerations, regulatory insights, and a growing online patient registry. In addition all three Research Projects will be supported by a single Vector Core that will undertake process development, production, and characterization of vectors. The final determination of our lead project will be made at the end of Year 2 based on side-by-side assessments of potency, dose responsiveness, brain biodistribulion, lime to effect and durability, off target outcomes, and tolerability; at least one follower project will also continue to be optimized through the end of the program to provide a backup option should the lead modality fail to perform as expected. Throughout the project, our Administrative Core will coordinate communication between Projects and data, model and protocol sharing with TCDC and the SGCE community, and a Scientific Advisory Board selected to represent disease-specific clinical and patient perspectives as well as private and academic sector drug development experience will be convened annually to advise on the progress of the program to ensure swift progress towards an effective therapeutic.