Wednesday, December 4, 2024
12/4/2024
Prion disease is a uniformly fatal, incurable neurodegenerative disease that causes 1 in every 6,000 deaths and typically leads to rapidly progressive dementia and death within less than half a year of first symptom. The various subtypes of prion disease including Creutzfeldt-Jakob disease, fatal familial insomnia, and Gerstmann-Straussler-Scheinker disease are all unified by a single molecular mechanism: misfolding of the prion protein (PrP) in the brain. PrP, encoded by the gene PRNP, is not pathogenic in its native form and is present in the brains of all mammals. But it is capable of undergoing a conformational change into a prion which spreads by corrupting other PrP molecules, eventually causing neuronal damage and death. Decades worth of research supports lowering PrP in the brain as a therapeutic strategy to prevent or delay onset, and slow the progression, of prion disease, and PrP appears to be dispensable for healthy life. However, finding a therapeutic modality with sufficient brain distribution, potency, durability, and tolerability to achieve adequate suppression of PrP in this relentlessly progressive whole brain disease is a major challenge. Divalent siRNA (di-siRNA) technology, first described in 2019, is a new class of chemically modified oligonucleotide therapeutic that can provide broad, deep, persistent suppression of target RNA molecules in the brain. Here we propose to develop a di-siRNA lead compound against the human PRNP RNA as a therapeutic for prion disease. In this project we will implement a manufacturing process, scale production, and perform quality testing of our lead di-siRNA, validate bioanalytical assays needed for animal and human studies of the compound, perform pharmacology and toxicology studies needed to support clinical development of a drug, and engage with the U.S. Food and Drug Administration to establish a development path for di-siRNA. Success in this project will yield a drug candidate with the potential to transform therapy of human prion disease.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
