Mar 31, 2020

Prion protein lowering is a disease-modifying therapy across prion strains, disease stages, and endpoints

BioRxiv : the Preprint Server for Biology
Avraam TapinosSonia M Vallabh


Lowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in prion disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays disease onset in intracerebrally prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional prion strains, with no evidence for the development of drug resistance. We demonstrate that less than 25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Both neuroinflammation measured through live animal bioluminescence imaging and neuronal injury measured by plasma neurofilament light chain can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change in these biomarkers. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of ne...Continue Reading

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Mentioned in this Paper

Sequence Analysis
Comparative Genomic Analysis
Instrument - Device
Sequence Determinations, DNA
Base Sequence

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