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Inhibiting Misfolded protein PRopagation in Neurodegenerative Diseases - Sofia ref.: 116060

Periodic Reporting for period 3 - IMPRiND (Inhibiting Misfolded protein PRopagation in Neurodegenerative Diseases - Sofia ref.: 116060)

Reporting period: 2019-03-01 to 2020-02-29

Over seven million people in Europe suffer from neurodegenerative diseases and this number is predicted to double by 2030 due to our increasingly ageing population with a dramatic impact on social services and potentially unsustainable financial burden on healthcare providers. Such urgent and currently unmet clinical need requires an unprecedented research effort that can only be achieved through a coordinated approach across leading European laboratories, the pharmaceutical industry and other international initiatives.
A growing body of data indicates that the propagation of pathogenic protein aggregates across neural systems could be mediated by misfolded protein seeds that are released and taken up by anatomically connected neurons causing disruption of their function. Therefore, blocking this process may help arrest the progression of Parkinson’s (PD) or Alzheimer’s (AD) disease. The Consortium IMPRiND, funded by the Innovative Medicine Initiative (IMI), is a group of European academic laboratories and members of the European Federation of Pharmaceutical Industries and Associations (EFPIA) that aims to delineate and target critical steps in the propagation of α-synuclein and tau assemblies between neurons. Our programme is collaborative and mobilizes diverse expertise in order to deliver physiologically relevant phenotypes suitable for screening and validation platforms in cellular systems of increasing complexity as well as animal models.
Over the third year, we have made significant progress in delivering on our objectives. This has been facilitated by regular teleconferences and one face-to-face Consortium meeting that took place alongside the International a-Synuclein meeting in Porto.

The research efforts in the second year were focused on three main areas: (i) completion of the CRISPR screens and primary neuronal screens, (ii) initial prioritisation of targets based on bioinformatic integration of screens, druggability and gene expression data, (iii) characterisation of advanced in vitro models or animals for validation and (iv) Data dissemination.

(i) A major effort has been invested in the completion of primary screens by UOXF, Novartis and HLU. These include focused CRISPR/Cas9 proteostasis screens for Syn and Tau, genome-wide CRISPR screens for tau, primary neuronal screens using siRNA for 300 targets for Tau and the DUB screen for Syn.
(ii) Hits from these screens were further analysed in an integrated fashion by Lilly to prioritise hits for further validation in advanced in vitro models or animals. Initial cross validation of hits has been performed at Novartis and HLU whereas UBx and Janssen planned assays in primary neurons for Syn and tau respectively.
(iii) A number of advanced models have been fully characterised and their suitability for further use has been established. These include the iPSC-based dopaminergic neuronal model (UOXF), organotypic cultures (DZNE) and in vivo mouse (BRFAA) or Zebrafish (Servier) models for Syn. The transplantation of iPSC-derived neurons for in vivo assessment of Tau propagation has also been completed. iPSC-based organoids (UCAM), hNP-based tau neuronal model (DZNE)and the primate model (UBx) are on-going.
(iv) These efforts are buttressed by the creation of a roadmap for a FAIR-driven data management policy with input from all members of the consortium. UOXF has developed an on-line study registry for standard operating procedures, critical reagents and significant results from IMPRiND with a view to enable sharing of datasets or dissemination following publications.

Website updates and news, social media messages, and a number of conference presentations and posters have completed the dissemination activities.
Through genetic screening and validation platforms IMPRiND will define critical steps in the propagation of alpha-synuclein and tau assemblies between neurons that could inform the development of mechanism-based future therapeutics.

This project receives funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 116060. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

This work is supported by the Swiss State Secretariat for Education‚ Research and Innovation (SERI) under contract number 17.00038.

The opinions expressed and arguments employed herein do not necessarily reflect the official views of these funding bodies.
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