Abstract Details

Title Development of antisense oligonucleotides for prion disease

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) S9 - Aging and Dementia: Clinical Trials and Novel Therapies (4:03 PM-4:14 PM)

Poster/Presentation
Number 004

Background Prion disease is a rapidly fatal, currently untreatable neurodegenerative disease caused by post-translational misfolding of the prion protein or PrP, into a self-propagating conformer. Strong genetic proofs of concept support the therapeutic strategy of reducing PrP expression in the brain.

Objective We assess the efficacy of prion protein (PrP)-lowering antisense oligonucleotides (ASOs) against prion disease in mice. We further evaluate the technical and biological suitability of PrP in human cerebrospinal fluid (CSF) to serve as a pharmacodynamic biomarker to support clinical advancement of ASOs for prion disease.

Design/Methods To test ASO efficacy, mice at two independent sites received bolus doses active ASOs, non-targeting control ASO, or saline either 1) before inoculation with prions, or 2) at a timepoint corresponding to established brain pathology. Additional in vivo experiments tested dose-responsiveness and efficacy against five distinct prion strains. All ASOs were delivered by stereotactic intracerebroventricular injection and mice were monitored for symptoms with a primary outcome of terminal prion disease. To evaluate CSF PrP as a biomarker for PrP-lowering therapeutics, N=253 human CSF samples spanning a range of diagnoses and prion disease subtypes were subjected to PrP quantification by ELISA.

Results Bolus dosing of PrP-lowering ASOs, but not non-targeting controls, delays onset of prion disease by 60-80% prophylactically and extends survival by ~60% when administered against established infection, consistent across both study sites. This survival benefit is dose responsive and universal across all prion strains tested. CSF PrP is detectable in all CSF samples tested, reliably quantifiable by ELISA subject to proper handling, appears CNS-derived, and exhibits excellent short-term within-subject test-retest stability (mean CV = 6%) in carriers of high-risk genetic prion disease mutations, a key trial population of interest.

Conclusions

These data support advancement of PrP-lowering ASOs to the clinic for prion disease.

Authors/Disclosures
Sonia M. Vallabh, PhD (Broad Institute) PRESENTER	No disclosure on file
Eric V. Minikel, PhD (Broad Institute of MIT and Harvard)	No disclosure on file
Hien Zhao	No disclosure on file
Holly Kordasiewicz	Holly Kordasiewcz has received personal compensation for serving as an employee of Ionis. Holly Kordasiewcz has stock in Ionis.
	No disclosure on file
Steven E. Arnold, MD (Massachusetts General Hospital)	Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EIP Pharma. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sage Therapeutics. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cortexyme. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Boyle Shaughnessy Law. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Wolf Greenfield. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Advisory Board Member with Bob's Last Marathon.

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