Research Core (Deverman)

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ABSTRACT — RESOURCE CORE Prion disease is a fatal, untreatable neurodegenerative disease caused by the prion protein (PrP). PrP, encoded by the chromosomal gene PRNP and expressed ubiquitously in all mammals, is not pathogenic in its native state, but causes disease when it misfolds into a "prion" capable of conformationally corrupting other PrP molecules. The goal, uniting all arms of this proposal, is to develop a single-dose, permanent PrP-lowering gene therapy to treat, prevent, or delay prion disease. Our multi-disciplinary team combines the leadership of committed patient-scientist, prion biologist and lead PI Sonia Vallabh with the cutting-edge expertise pertaining to base editing from the David Liu Group, epigenome editing from the Jonathan Weissman Lab, and delivery vector engineering and manufacturing from the Ben Deverman Lab, which will serve as the Vector Core. Cross-cutting all areas of this proposal is the need for vectors that can achieve dramatically enhanced CNS gene delivery for this whole brain disease in human patients as well as preclinical models. This need makes critical the integration of new breakthroughs in delivery vector engineering as well as expertise in vector biology, production, quality control, and characterization. Through other ongoing, fully funded projects, the Deverman lab has engineered improved delivery vectors for the CNS and established a platform for systematically identifying additional vectors with multiple traits relevant to gene therapy. This proposal will apply the top candidates from these ongoing projects to the development of a PrP-lowering gene therapy. The Vector Engineering Resource Core led by Dr. Deverman will undertake process development, production, formulation, and characterization of delivery vectors in support of the in vivo studies for all three projects in this proposal; assist with tissue handling and biodistribution analysis; develop a scalable production and analytical pipeline, and provide technology transfer and oversight for at-scale manufacturing. In the context of this overall proposal, the Resource Core will underpin the core goal of transforming prion disease therapy with a single- dose therapy, and also provide a foundational proof-of-concept for the application of engineered delivery vectors toward systemically-administered CNS gene therapy in adult human patients.