cadth 2015 c5 1. cashman rare diseases

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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

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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