Antisense Oligonucleotides for the Prevention of Genetic Prion Disease
Vallabh, Sonia Minikel
MetadataShow full item record
CitationVallabh, Sonia Minikel. 2019. Antisense Oligonucleotides for the Prevention of Genetic Prion Disease. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractHuman 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.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42029697
- FAS Theses and Dissertations