dc.contributor.advisor | Haggarty, Stephen | |
dc.contributor.author | Vallabh, Sonia Minikel | |
dc.date.accessioned | 2019-12-12T09:00:04Z | |
dash.embargo.terms | 2020-05-01 | |
dc.date.created | 2019-05 | |
dc.date.issued | 2019-05-13 | |
dc.date.submitted | 2019 | |
dc.identifier.citation | Vallabh, Sonia Minikel. 2019. Antisense Oligonucleotides for the Prevention of Genetic Prion Disease. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences. | |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:42029697 | * |
dc.description.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. | |
dc.description.sponsorship | Medical Sciences | |
dc.format.mimetype | application/pdf | |
dc.language.iso | en | |
dash.license | LAA | |
dc.subject | Genetic prion disease | |
dc.subject | prion disease | |
dc.subject | Creutzfeldt-Jakob disease | |
dc.subject | CJD | |
dc.subject | fatal familial insomnia | |
dc.subject | FFI | |
dc.subject | Gerstmann-Straussler-Scheinker disease | |
dc.subject | GSS | |
dc.subject | therapeutic development | |
dc.subject | antisense oligonucleotides | |
dc.subject | ASOs | |
dc.subject | cerebrospinal fluid | |
dc.subject | CSF | |
dc.subject | biomarker | |
dc.subject | natural history | |
dc.subject | prevention | |
dc.subject | neurodegeneration | |
dc.title | Antisense Oligonucleotides for the Prevention of Genetic Prion Disease | |
dc.type | Thesis or Dissertation | |
dash.depositing.author | Vallabh, Sonia Minikel | |
dash.embargo.until | 2020-05-01 | |
dc.date.available | 2019-12-12T09:00:04Z | |
thesis.degree.date | 2019 | |
thesis.degree.grantor | Graduate School of Arts & Sciences | |
thesis.degree.grantor | Graduate School of Arts & Sciences | |
thesis.degree.level | Doctoral | |
thesis.degree.level | Doctoral | |
thesis.degree.name | Doctor of Philosophy | |
thesis.degree.name | Doctor of Philosophy | |
dc.contributor.committeeMember | Talkowski, Michael | |
dc.contributor.committeeMember | Watts, Joel | |
dc.contributor.committeeMember | Ghaemmaghami, Sina | |
dc.type.material | text | |
thesis.degree.department | Medical Sciences | |
thesis.degree.department | Medical Sciences | |
dash.identifier.vireo | | |
dc.identifier.orcid | 0000-0003-3824-2702 | |
dash.author.email | sonia.vallabh@gmail.com | |