Antisense Oligonucleotides for the Prevention of Genetic Prion Disease

Abstract

Human prion disease is a fatal, currently untreatable neurodegenerative disease. Across subtypes – which include Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), and Gerstmann-Straussler-Scheinker disease (GSS) – all cases are caused by the conformational corruption of the prion protein, or PrP, into a self-templating proteinaceous pathogen known as a prion. Strong genetic proofs of concept support the therapeutic strategy of reducing PrP expression in the brain, and plausible modalities to effect this reduction are now emerging. Pre-symptomatic carriers of high-risk genetic prion disease mutations can be identified in advance of symptoms, providing an opportunity for early therapeutic intervention to extend healthy life. Here we provide a set of tools to enable meaningful trials of PrP-lowering therapeutics in pre-symptomatic genetic prion disease mutation carriers. First, we outline a regulatory strategy to support meaningful testing of PrP-lowering therapeutics in healthy carriers, leveraging PrP levels in cerebrospinal fluid (CSF) as a surrogate endpoint. The U.S. Food and Drug Administration (FDA) Accelerated Approval pathway provides a potentially appropriate mechanism, and we describe regulatory engagement to this effect. Second, we report prophylactic efficacy of PrP-lowering ASOs in prion-infected mice. We show that administration of ASOs prior to prion infection extends life by delaying disease onset across a variety of paradigms. This benefit is dose-responsive and universal against all prion strains tested. Third, we assess the technical and biological suitability of CSF to serve as a biomarker for therapeutic reduction of PrP in the brain. We show that PrP in human CSF can be reliably quantified, reflects the tissue of interest, and exhibits reasonable short-term within-subject stability. Fourth, we describe a natural history study of pre-symptomatic genetic prion disease mutation carriers. We validate the short-term within-subject stability CSF PrP levels in this trial population of interest. We also show that pre-symptomatic carriers have normal levels of key prion disease-associated fluid biomarkers, supporting the need for a primary prevention strategy. Our findings provide a therapeutic and clinical strategy for prevention of genetic prion disease.