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Selectively targeting gamma-secretase

The incidence of Alzheimer’s disease (AD) is continuing to rise, however with no disease modifying treatments currently available, a rational approach to developing therapeutics is required, for example targeting enzymes that generates the amyloid-beta protein (Aβ). The build-up of Aβ in the AD brain occurs early in the disease process and two enzymes, BACE and gamma-secretase (“g-sec”) are known to lower the production of Aβ but have shown side-effects in clinical trials leading to safety concerns.

Despite this, “g-sec” is still a worthy target as unlike BACE, it directly generates Aβ and could potentially be targeted to selectively reduce neurotoxic forms of Aβ. The major problem is that the current drugs are designed to reduce overall enzyme activity, thereby targeting the activities of this enzyme in normal cell function and resulting in off-target effects. More selective targeting is required.

Recent evidence shows that multiple versions of “g-sec” with different activities exist. On this basis, researchers at Curtin University’s School of Biomedical Sciences have identified regions of the presenilins, are important for enzyme activity and certain combinations of these areas are involved in Aβ production, compared to its other activities.

The proposed project will use a combination of lab based experiments and computer modelling to refine and pinpoint targets within presenilins (PS-1 and -2) responsible for Aβ production. This will ultimately offer potential targets for designing more selective small molecule therapeutics aimed at treating AD by slowing down or preventing build-up of pathogenic Aβ.

Advantages

Our approach offers the following advantages:

  • selectively target g-sec regions for Aβ
  • reduce or eradicate NOTCH-mediated off target effects
  • use of molecular modelling to refine approach
  • validate new targets in AD
  • informs drug discovery strategies
  • in vivo Zebrafish model

Researchers

Associate Professors Giuseppe Verdile and David Groth are cell and molecular biologists from the Curtin Health Innovation Research Institute who lead the team. They are supported by Dr Mark Agostino, a molecular modeller. Each team member has experience working to deliver research outcomes with impact to industry. The project has major collaborators at University of Toronto (Professor Paul Fraser) and University of Adelaide (Associate Professor Michael Lardelli) and University of Bristol (Professor Imre Berger).

Stage of development

Initial results show that chimeras created by substituting domains from PS-1 and PS-2 has created a selectively active g-sec which processes Aβ precursor protein (APP) in favour of NOTCH (associated with off target effects). Targeted modulation of APP is the focus of continued refinement with a view to identifying new binding sites relevant to AD, against which new drugs can be screened.

Opportunity

Curtin is seeking partners to support the further research and development into the targets and their validation, with a view to performing drug screening for new AD therapeutics.

Contact

Russell Nicholls – Deputy Director, Commercialisation, Curtin University

Email: russell.nicholls@curtin.edu.au

Phone: +61 410 285554