CADTH 2015 Symposium

1. Neurodegenerative Diseases:
The Distorted Origami of Protein Misfolding
Neil R. Cashman MD
Professor and Canada Research Chair
Brain Research Centre
Department of Medicine (Neurology)
University of British Columbia
Academic Director, ALS Centre
GF Strong Hospital

2. Caprion Pharmaceuticals
Founder and Scientific Advisor
(YYR PrPSc Epitope)
Amorfix Life Sciences
Founder 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

3. Cancer
Neurodegeneration
Cancer
Neurodegeneration
Disruptive Idea 1: Protein Misfolding and Disease

4. 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. 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 Immunoassay
AMFIA™ Quantifies Aβ in its monomeric form
Immunoassay sensitivity
Aβ-Disaggregation
ELUATE
(aggregated Aβ)
FLOW
(monomeric Aβ)
A4 Matrix
Capture and concentrate
Aβ aggregates
INPUT
Sample/homogenate
preparationBrain, plasma,
CSF, cell culture
0.01 0.1 1 10 100
1,000
2,000
4,000
8,000
16,000
32,000
64,000
128,000
256,000
512,000
A42
A40
28 fg 1.8 pg
assay bkgd
A (pg/well)
RFU

6. 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)

7. Acknowledgements
University of Toronto
Chakrabartty group
Pai group
Prosser group
U Sask – VIDO, PREVENT
Napper group
CIHR: III, IA, INMHA
ALS Canada
PrioNet 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