neurodegenerative diseases: the distorted origami of protein misfolding neil r. cashman md professor...
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Neurodegenerative Diseases: The Distorted Origami of Protein Misfolding
Neil R. Cashman MD
Professor and Canada Research ChairBrain Research Centre
Department of Medicine (Neurology)University of British Columbia
Academic Director, ALS CentreGF Strong Hospital
Caprion PharmaceuticalsFounder and Scientific Advisor
(YYR PrPSc Epitope)
Amorfix Life SciencesFounder and CSO, Chair BoD
(Epitope Protection, SOD1 Epitopes, ProMIS)
Biogen-Idec Corporation(SOD1 DSE Immunotherapy)
Cangene Corporation(Aβ Oligomer Epitope)
Prothena Biosciences(Scientific Advisory Board)
Industrial Engagement
Cancer
Neurodegeneration
Cancer
Neurodegeneration
Disruptive Idea 1: Protein Misfolding and Disease
Disruptive Idea 2: Antibodies Can Selectively Target Misfolded Proteins while Sparing Native Isoforms
Efficacy: Specific targeting of a pathogenic species– Neutralization of toxicity– Blockade of propagation– Acceleration of degradation– Minimal “target distraction”
Safety: Selective sparing of normal proteins– Preservation of normal function– Minimization of autoimmunity – Minimal regimens in therapeutic vaccines
5
Amorfix Aggregated Aβ Assay (A4): Test Overview
Part 1: Aβ Aggregate Isolation Part 2: Aβ Quantification
Disaggregated Aβ
Magnetic bead coupled to 1F8/2H12
Europium bead coupled
to 4G10
Aβ Ultra-Sensitive ImmunoassayAMFIA™ Quantifies Aβ in its monomeric form
Immunoassay sensitivity
Aβ-Disaggregation
ELUATE(aggregated Aβ)
FLOW(monomeric Aβ)
A4 MatrixCapture and concentrate
Aβ aggregates
INPUTSample/homogenate
preparationBrain, plasma, CSF, cell culture
0.01 0.1 1 10 1001,000
2,000
4,000
8,000
16,000
32,000
64,000
128,000
256,000
512,000
A42A40
28 fg 1.8 pg
assay bkgd
A (pg/well)
RF
U
Propagated Protein Misfolding Diseases
ALS(aggregates)
Parkinson’s diseases(Lewy Bodies)
Alzheimer’s diseases(plaques and tangles)
Prion diseases(PrP amyloid plaques)
Huntington’s disease (aggregates)
TTR amyloid neuropathy
(plaques)
Schizophrenia(aggregates)
Type 2 diabetes (aggregates)
Acknowledgements
University of Toronto Chakrabartty group Pai group Prosser group
U Sask – VIDO, PREVENT Napper group
CIHR: III, IA, INMHAALS CanadaPrioNet Canada Canada Research Chairs CFI & BCKDF
Cangene/Emergent Corp
UBC Cashman group Plotkin group Mackenzie group Jia group Marziali group Wang group Wellington group
University of Alberta Wishart group Kovalenko group
Amorfix Life Sciences