好色先生

好色先生

Explore the latest content from across our publications
Join The AAN

Log In

Forgot Password?
Create New Account

Loading... please wait

Abstract Details

Evaluation of Fluid Biomarkers for Use in Clinical Trials in Individuals at Risk for Prion Disease
Aging, Dementia, and Behavioral Neurology
S23 - Aging and Dementia: Biomarkers and Clinical Trials (4:06 PM-4:18 PM)
004
To evaluate cerebrospinal fluid (CSF) and plasma biomarkers for use in trials of prion protein (PrP)-lowering drugs in pre-symptomatic individuals at high risk for genetic prion disease.
Antisense oligonucleotides (ASOs) to lower PrP are currently in preclinical development. Identification of biomarkers associated with early disease signs or with ASO mechanism-of-action may facilitate clinical testing in pre-symptomatic individuals.
Pre-symptomatic mutation carriers (N=27) and mutation-negative controls (N=16) made multiple visits to a clinical research study at Massachusetts General Hospital to donate CSF and blood for evaluation of biomarkers cross-sectionally and longitudinally over 2 to 20 months. Pharmacodynamic studies were conducted in mice and rats using intracerebroventricular dosing of a PrP-lowering antisense oligonucleotide. PrP RNA was measured by qPCR and PrP protein was measured by ELISA and mass spectrometry.
CSF PrP concentration was stable (mean CV=7%) over up to 20 months in both mutation carriers and controls. CSF prion “seeds” measured by real-time quaking induced conversion (RT-QuIC) were observed in one pre-symptomatic carrier. Neuronal damage markers neurofilament light chain (NfL) and total tau were within the normal range for all participants and were indistinguishable between mutation carriers and controls in both CSF and plasma in this study. Pharmacodynamic models were constructed to relate target engagement in brain to that in CSF in rodent models.

CSF PrP levels were stable over time, supporting their use as a target engagement marker in trials of PrP-lowering agents in pre-symptomatic individuals. PrP mutation carriers exhibited normal NfL and tau profiles in this study, and all but one were negative by RT-QuIC, suggesting these endpoints may not be able to serve as primary endpoints in trials in pre-symptomatic individuals. If further observation reveals abnormalities in these or other markers, use as exploratory endpoints in clinical trials in pre-symptomatic individuals may be warranted.
Authors/Disclosures
Eric V. Minikel, PhD (Broad Institute of MIT and Harvard)
PRESENTER 		No disclosure on file
Victoria Williams (Institute of Psychiatry) No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
Hien Zhao No disclosure on file
Kaj Blennow Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AC Immune. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ALZPath. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AriBio. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Beckman-Coulter. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BioArctic. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lilly. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Moleac Pte. Ltd. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurimmune. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ono Pharma. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Prothena. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Quanterix. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche Diagnostics. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Siemens Healthineers. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbvie. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AC Immune. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ALZPath. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AriBio. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Beckman-Coulter. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BioArctic. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lilly. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Moleac Pte. Ltd. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neurimmune. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Ono Pharma. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Prothena. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Quanterix. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche Diagnostics. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Siemens Healthineers. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Julius Clinical. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for AC Immune. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Celdara Medical. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Eisai. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche Diagnostics. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Co-founder with Brain Biomarker Solutions.
Henrik Zetterberg (Sahlgrenska University Hospital/Molndal) Henrik Zetterberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave. Henrik Zetterberg has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD. Henrik Zetterberg has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Wiley and Elsevier. Henrik Zetterberg has stock in Brain Biomarker Solutions.
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.
Sonia M. Vallabh, PhD (Broad Institute) An immediate family member of Dr. Vallabh has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Deerfield. Dr. Vallabh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alnylam Pharmaceuticals. An immediate family member of Dr. Vallabh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alnylam Pharmaceuticals. An immediate family member of Dr. Vallabh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Abbvie. An immediate family member of Dr. Vallabh has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Eli Lilly & Co.. An immediate family member of Dr. Vallabh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Vertex. An immediate family member of Dr. Vallabh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Voyager Theapeutics. Dr. Vallabh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Abbvie. Dr. Vallabh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Eli Lilly & Co.. Dr. Vallabh has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Voyager Therapeutics. The institution of Dr. Vallabh has received research support from Eli Lilly & Co.. The institution of Dr. Vallabh has received research support from Gate Bioscience. The institution of Dr. Vallabh has received research support from Ionis Pharmaceuticals. The institution of Dr. Vallabh has received research support from Sangamo. Dr. Vallabh has a non-compensated relationship as a President with Prion Alliance that is relevant to AAN interests or activities.