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

  • Project Leaders: David Vocadlo
  • Institutions: Simon Fraser University (SFU)
  • Budget: $1500000
  • Program/Competition: Partner Programs
  • Genome Centre(s): Genome British Columbia
  • Fiscal Year: 2014
  • Status: Closed

No medications exist that can stop or even slow the progression for Alzheimer Disease (AD). 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. OGA inhibitors have been shown to block disease progression in animal models of Alzheimer Disease (AD) by blocking the toxicity of both Aβ and tau. The hypothesis is that O-GlcNAc is protective in AD and acts by enhancing brain autophagy. OGA is known to remove O-GlcNAc in humans. OGA inhibitors show no toxicity, which makes them well-suited to be therapeutics. The main goal of this project is to advance this new potential approach towards clinical implementation. This will be done by optimizing the promising new lead inhibitors to have desirable drug like properties that would make them suitable for use in humans, define the mechanism by which these lead molecules block tau and Aβ toxicity, verify efficacy in AD mouse models, identify biomarkers to support entry of these molecules into the clinic, and link markers of disease and efficacy in mouse models to markers in human AD tissues. These findings will enable the rapid advance of these optimized molecules into formal toxicology studies and downstream trials.