Report
Teaser, summary, work performed and final results
Periodic Reporting for period 2 - IMPRiND (Inhibiting Misfolded protein PRopagation in Neurodegenerative Diseases - Sofia ref.: 116060)
Teaser
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...
Summary
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.
Work performed
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 second year, we have made significant progress in delivering on our objectives. This has been facilitated by regular teleconferences and two face-to-face Consortium meetings, one hosted by Eli Lilly in the UK and a recent meeting held in Lisbon before the International ADPD Congress. We have also organised our first International Symposium on proteopathic assemblies which took place at the ADPD Congress featuring both internal (Michel Goedert, Dieder Moechars) and external (Virginia Lee, Dominic Walsh) speakers and a panel discussion with questions from the audience. This proved to be an enjoyable and informative evening with a large number of attendees (>500).
The research efforts in the second year were focused on five main areas: (i) successful generation of brain-derived or amplified assemblies and their initial characterisation in cellular models, (ii) Cryo-EM structure of tau assemblies from different tauopathies, (iii) completion of two focused CRISPR-based screens for -synuclein and tau, (iv) further characterisation of validation models, (v) development of the data management plan. Specific progress along these lines that also demonstrates our collaborative approach include the following:
i. LMB, Lilly and Janssen have optimised and cross-validated protocols to isolate and quality control brain-derived tau assemblies from Alzheimer’s disease brain. CNRS has established methodologies for amplification of proteopathic assemblies from brain homogenates of alpha-synucleinopathy cases, which have undergone initial characterisation in cellular models at UOXF and HLU.
ii. LMB has published the Cryo-EM structures of tau filaments isolated from Alzheimer’s disease, Pick’s disease and chronic traumatic encephalopathy (Nature, 2017, 2018, 2019) as well as Cryo-EM structures of heparin-induced tau filaments.
iii. UOXF, UCAM and Novartis have worked collaboratively to complete the first focused CRISPR/Cas9 screens for modifiers of tau aggregation or alpha-synuclein levels. UOXF with Novartis have already developed a pipeline for a screen on alpha-synuclein aggregation.
iv. A number of neuronal and animal models are in advanced stages of characterization and suitable for target validation. These include iPSC-based neuronal models (UOXF) or organotypic cultures (DZNE) for alpha-synuclein or animal models for tau (Lilly and Janssen). Additional studies in hNP-based cellular models (DZNE), primary neurons (HLU, UBX), flies (VIB), zebrafish (Servier), mice (HLU, VIB, BRFAA) and primates (UBx) are on-going.
v. 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 completed previous study surveys and 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.
The collaborative work carried out in IMPRiND resulted so far in 13 publications, amon
Final results
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.
Website & more info
More info: http://imprind.org/.