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Preclincal development of a disease modifying small molecule therapy for Alzheimer disease.

Principal Investigator:
  • David Vocadlo, Simon Fraser University
Team Members:
  • Gideon Davies, York University
  • Sharon Gorski, Simon Fraser University
  • Leonard Foster, University of British Columbia
  • Cheng-Xin Gong, Institute for Basic Research in Developmental Disabilities
  • Ian Mackenzie, University of British Columbia
  • Howard Feldman, University of British Columbia
  • Michael Silverman, Simon Fraser University
  • Ging-Yuek Hsiung, University of British Columbia
  • Robert Britton, Simon Fraser University
  • Cheryl Wellington, University of British Columbia
  • Michael Smith Foundation for Health Research
  • Genome BC
  • Pacific Alzheimer's Research Foundation

Project Overview

No medications exist that can stop or even slow the progression for Alzheimer Disease (AD). Several dramatic late stage clinical failures have heightened recognition that novel approaches need to be quickly pursued in order to develop useful treatments for the aging population. The two pathological hallmarks of AD are protein aggregates deposited in the brain that are known as tangles and plaques. These aggregates form from inappropriately modified forms of the microtubule associated protein tau and peptide fragments, known as Aβ which are generated by cleavage of the amyloid precursor protein. We have recently pioneered a new potential approach that has been shown to block disease progression in animal models of AD by blocking the toxicity of both of Aβ and tau. Our approach centers on a specialized sugar unit that is found attached to nuclear and cytoplasmic proteins, including both tau and APP. Our multidisciplinary team now aims to address the key remaining challenges that would clear the way for a promising new therapeutic target to advance to the clinic. Specifically, we aim to, (i) optimize promising new lead molecules to have desirable drug like properties that would make them suitable for use in humans, (ii) define the mechanism by which these lead molecules block tau and Aβ toxicity, (iii) verify proof-of-concept using this new optimized lead molecule in AD mouse models, (iv) identify biomarkers to support entry of these molecules into the clinic, and (v) link markers of disease and efficacy in mouse models to markers in human AD tissues. By accomplishing these specific aims we will have a potential clinical candidate that will be well supported with an understanding of the mechanism of action as well as useful biomarkers. These findings will enable the rapid advance of these optimized molecules into formal toxicology studies and downstream trials.