WNT signaling: biomarker and target evaluation in Alzheimer's disease
Lead Research Organisation:
University of Oxford
Department Name: Psychiatry
Abstract
The invariant failure of Biopharmaceutical pipelines to modify Alzheimer's
disease (AD) progression indicates the need for new creative solutions beyond
currently active areas of genetics, amyloid-ß, and Tau pathology. Very recent work
from our groups and others indicate that novel elements of the canonical and noncanonical WNT signaling pathways could be targeted to modify and monitor AD
progression.
In this project we will use multidisciplinary approaches, including brain oriented drug screening, a novel proprietary mouse model of AD, new genetic and pharmacological tools for modulation of WNT/GSK3 and WNT/JNK pathways, human
blood samples from our and the IMI/EMIF platform to identify novel biomarkers of AD progression and a pilot study on metabolomics, to explore the impact on AD of
novel WNT elements including but not limited to clusterin, DKK1 and Nrf2.
Our results in this pathfinder phase with the identification of new candidate targets and drugs for clinical studies will pave the way to therapeutic innovations in
the long-term programme. Indeed, several Biopharma companies have initiated drug development programs aimed at targeting certain components of the WNT signaling pathway, including ligands and other small molecule regulators of Axin1 and GSK-3, and Nrf2 that will be interested in our findings.
disease (AD) progression indicates the need for new creative solutions beyond
currently active areas of genetics, amyloid-ß, and Tau pathology. Very recent work
from our groups and others indicate that novel elements of the canonical and noncanonical WNT signaling pathways could be targeted to modify and monitor AD
progression.
In this project we will use multidisciplinary approaches, including brain oriented drug screening, a novel proprietary mouse model of AD, new genetic and pharmacological tools for modulation of WNT/GSK3 and WNT/JNK pathways, human
blood samples from our and the IMI/EMIF platform to identify novel biomarkers of AD progression and a pilot study on metabolomics, to explore the impact on AD of
novel WNT elements including but not limited to clusterin, DKK1 and Nrf2.
Our results in this pathfinder phase with the identification of new candidate targets and drugs for clinical studies will pave the way to therapeutic innovations in
the long-term programme. Indeed, several Biopharma companies have initiated drug development programs aimed at targeting certain components of the WNT signaling pathway, including ligands and other small molecule regulators of Axin1 and GSK-3, and Nrf2 that will be interested in our findings.
People |
ORCID iD |
| Simon Lovestone (Principal Investigator) |
Publications
Rojo AI
(2017)
NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology.
in Redox biology
| Description | Collaboration with Andrey Voronkov/DigitalBiopharma |
| Organisation | Digital BioPharm Ltd |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | We have formed a collaboration to screen for compounds from a pipeline developed for oncology. We will perform in depth phenotypic and other screens |
| Collaborator Contribution | Our partners will provide compounds with established PK/PD suitable for repurposing |
| Impact | Screens performed and data deconvolution underway |
| Start Year | 2016 |
| Description | Collaboration with Fraunhofer and AETIONOMY |
| Organisation | Fraunhofer Society |
| Department | Fraunhofer Institute for Algorithms and Scientific Computing |
| Country | Germany |
| Sector | Public |
| PI Contribution | We have established a collaboration with Martin Hoffmann-Apitius at Fraunhofer SCAI with funding from UCB via the AETIONOMY programme. The funding is an estimate at present and is for a post-doctoral research worker for two years. The collaboration is to utilise the datasets we have generated together with our access to and knowledge of EHRs. We will also contribute informatics expertise and deep learning/neural networks to the collaboration. UPDATE JAN 2018; we have also agreed to share biomolecular data including proteomics with our partners in Fraunhofer, extending our collaboration and leveraging resources from both sites to accelerate our understanding of AD and PD and developing novel biomarkers |
| Collaborator Contribution | The Franunhofer / AETIONOMY group have generated a systems approach to determining pathways and mechanisms in neurodegeneration and we will work together utilising their Big Data analytics and tools and our Neural Networks/NLP approach and data to validate and extend their models. |
| Impact | Too soon for outcomes |
| Start Year | 2016 |
| Description | Further target development |
| Organisation | University of Oxford |
| Department | Alzheimer's Research UK Oxford Drug Discovery Institute |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | We have developed assays, proof of concept and in vivo and in vitro models for drug development in wnt signalling pathways for dementia therapies |
| Collaborator Contribution | The ARUK DDI has selected this work for further development with the objective of identifying therapeutic compounds |
| Impact | n/a |
| Start Year | 2016 |