AETIONOMY

Organising mechanistic knowledge about neurodegenerative diseases for the improvement of drug development and therapy

Summary

AETIONOMY came up with innovative way to classify neurodegenerative diseases Alzheimer's (AD) and Parkinson's (PD) based on the mechanism i.e. cause(s) of disease. The project developed a prototype for a taxonomy that will change how we look at the drivers of these diseases. The curated data, tools and mechanistic hypotheses can enable drug developers and regulators direct the development, approval and use of new diagnostic tests and treatments for both diseases.

Today, diseases are still defined largely based on signs and symptoms, yet while two patients may share the same diagnosis, the underlying causes of their symptoms may be very different. Naturally, this means that a treatment that works in one patient may prove ineffective in another. There is now broad acceptance that a new direction for disease classification is needed, built not on symptomatology, but derived from the mechanisms, or causes, that drive the disease.

Prototype taxonomy and a knowledge base

The AETIONOMY team started by tackling the problem of how to obtain, organise, structure, integrate and interpret a broad range of data (ranging from molecular data, to information on symptoms) from the neurodegeneration community. They then ‘dissected’ the underlying mechanistic causes in order to bring structure to their classification; linking the mechanistic causes to clinical evidence in an attempt to validate them.

The consortium demonstrated that their prototype taxonomy can be used to identify patient subgroups in PD. They were able to perform a partial validation of a selection of candidate mechanisms for both diseases. The validation was done in-silico and by means of dedicated wet lab experiments performed by clinical research, biotech and pharmaceutical partners.

AETIONOMY resulted in an open-access knowledge base with inventories of mechanistic hypotheses; these form the basis for the prototype taxonomies for both AD and PD. The knowledge base also contains curated clinical and relevant OMICS-data (analysis of complete genetic or molecular profiles), disease models for AD and PD, analysis and visualisation, and data from participants of a cross-sectional clinical study and additional integrated cohorts. The neurodegenerative research community now has access to the inventory of computable models, as well as a dedicated set of algorithms that can facilitate the interrogation of the mechanistic hypotheses against patient data.

Virtual data cohorts

AETIONOMY recruited a significant cohort of patients and controls, and coordinated the logistics of sample transfers and execution of a range of biomarker assays. The patient cohorts were profiled and characterised to a degree that allowed the consortium to perform ‘mechanism-enrichment’ procedures on patient-level biomarker data.

To overcome hurdles related to accessing patient data to carry out in-silico validation of disease mechanisms, the consortium developed the concept of virtual data cohorts (VDCs), which are artificial data sets that share features and characteristics of real-world study cohorts. VDCs have the potential to overcome some of the challenges inherent to translational neurodegeneration research, namely the sharing of patient-level data without compromising patient data privacy (but also other challenges, like merging heterogeneous, complex clinical data sets and more).

Through this conceptualisation and implementation of VDCs, the AETIONOMY project may pave the way for future data sharing and data integration of patient-level data without compromising patient privacy. The virtual patient topic was not a novel concept invented by the AETIONOMY consortium but is in line with globally emergent trends.

Collaboration and synergies

The project brought together 18 partners including pharmaceutical companies, universities, and patient groups, and combined substantial expertise in neurodegenerative diseases, molecular biology, clinical research, research ethics and law, neuroimaging, data modelling and simulation, data standards, and patient engagement in research among others.

Collaborations, beyond the original scope of the project but initiated through the identification of common goals, were key for the project’s success; in particular, collaborations with the University of Oxford and the Human Brain Project. Working with Alzheimer Europe, AETIONOMY had the valuable opportunity to network with leading European researchers in the field and to help ensure that the perspectives of people with dementia were taken into consideration.

The consortium is still (partially) alive

Part of the AETIONOMY consortium is still working together; Fraunhofer SCAI (Institute for Algorithms and Scientific Computing) in Germany and the ICM (Institute for Brain and Spinal Cord) in France have collaborated since the official end of the funded period. Based on an initial workshop in Bonn on longitudinal modelling of disease progression, the collaborators decided to make the workshop a regular event that reaches out to other projects at EU level, including the IMI project RADAR-AD and the Horizon 2020 initiative, the Virtual Brain Cloud. Work in AETIONOMY has thus led to a major collaborative effort to understand the dynamics of neurodegenerative disease progression. Other collaborative efforts that have been sustained concern the topic of information extraction for model generation, where Frauenhofer SCAI have partnered with the University of Luxembourg (currently applied to the context of COVID-19).

Achievements & News

Alzheimer's researchers use AI to get access to brains

IMI’s AETIONOMY project used digital technology to simulate 'personalised' brains with individual 'wiring', allowing them to study processes associated with Alzheimer's. ‘How do we overcome the challenge of the inaccessibility of the human brain?’ asks to Professor Martin Hofmann-Apitius, academic lead of AETIONOMY, in an interview ###with the IMI Programme Office. ‘Actually, in-silico technologies help us to understand what is going on in the brain even before we can measure it directly by taking samples from living people.’ The AETIONOMY project used digital technology to study brains without needing samples from living people, allowing them to simulate processes associated with Alzheimer's. In their mission to establish new ways of reclassifying Alzheimer’s and other neurodegenerative diseases, the team tackled the problem of how to obtain, organise, structure, integrate and interpret a broad range of distinct types of data, ranging from molecular data, to information on symptoms, available across the neurodegeneration community. They brought new structure to the classification of disease by dissecting the underlying mechanistic and molecular causes of disease, and by linking these to clinical evidence to attempt to partially validate a selection of these mechanistic drivers.

‘Humans like reductionist approaches - one cause, one reason. But there is reason to believe there are many causes of Alzheimer’s disease that may work in combination, and that was one of the biggest scientific challenges in AETIONOMY: the combinatorial causality, Professor Hofmann-Apitius concludes. ‘The task of AETIONOMY was to unravel this and I expect to see impact of our findings at least ten years down the line.’

Read more

IMI projects feature in new brochure on the brain and digital technologies

IMI projects are among those featured in a new brochure on how the digital revolution is transforming EU-funded brain research. The brochure, produced by CORDIS, was published to coincide with IMI’s Stakeholder Forum on the same subject. The IMI projects featured are AETIONOMY, EU-AIMS and PRISM. AETIONOMY systematically captures and represents knowledge on neurodegenerative diseases in a computable format that represents causes and effects and that can be analysed using algorithms. EU-AIMS has developed a large autism database, one of the richest of its kind in the world, which has the potential to drastically change the knowledge base for autism. Finally, PRISM has developed a new framework that would help researchers better understand the complexity of neuropsychiatric illness, moving away from current reductive disease classifications, to pave the way for new treatments.

IMI projects working on a new way of defining diseases

The work of IMI’s PRECISESADS and AETIONOMY projects on disease taxonomy is spotlighted in a new Nature Reviews Discovery comment piece.### Currently, most diseases are still defined largely on the basis of their symptoms, yet while two patients may share the same diagnosis, the underlying causes of their symptoms may be very different. This means that a treatment that works in one patient may prove ineffective in another. The AETIONOMY and PRECISESADS projects are pioneering a new approach to the classification of disease; for AETIONOMY, in the field of Alzheimer’s and Parkinson’s diseases, and for PRECISESADS, in the field of systemic autoimmune diseases (such as rheumatoid arthritis and lupus). Although the projects are tackling the problem in different ways, their overall goal is the same: to pave the way towards a new taxonomy of disease that is based on the underlying causes of disease. In the long term, this will help to diagnose patients more accurately and provide them with a treatment that works for them.

IMI scientist wins entrepreneurship award

The 2013 award for Hungarian Young Entrepreneur of the Year was won by Tamas Letoha, Chief Executive Officer of Pharmacoidea, which is a partner in two IMI projects.### Tamas was selected as the winner from over 400 public nominations from more than 50 small and medium-sized enterprises (SMEs) from a number of different business sectors. Dr Letoha, a medical researcher by training, received his award from the Hungarian Prime Minister, Viktor Orbán at the Role Model of the Year Award gala in January. The annual award is sponsored by the Role Model Foundation which was set up in 2013 to recognise successful Hungarian entrepreneurs under the age of 40. Tamas heads up Pharmacoidea Ltd. which specialises in R&D in drug discovery, functional food development and experimental cellular therapeutics against carcinomas.  Pharmacoidea is a partner in two IMI projects, COMPACT and AETIONOMY. Tamas said that his achievements ‘were pretty much due to international R&D projects like AETIONOMY ’ and that he highly valued his connections with IMI.

Participants

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EFPIA companies
  • Boehringer Ingelheim Internationalgmbh, Ingelheim, Germany
  • Novartis Pharma AG, Basel, Switzerland
  • Sanofi-Aventis Recherche & Developpement, Chilly Mazarin, France
  • UCB Biopharma, Brussels, Belgium
Universities, research organisations, public bodies, non-profit groups
  • Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Barcelona, Spain
  • Erasmus Universitair Medisch Centrum Rotterdam, Rotterdam, Netherlands
  • Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V., München, Germany
  • Fundacio Barcelonabeta Brain Research Center, Barcelona, Spain
  • Gottfried Wilhelm Leibniz Universitaet Hannover, Hannover, Germany
  • Institut Du Cerveau Et De La Moelle Epiniere, Paris, France
  • Karolinska Institutet, Stockholm, Sweden
  • Universitatsklinikum Bonn, Bonn, Germany
  • Universite D'Aix Marseille, Marseille, France
  • Universite Du Luxembourg, Esch-sur-Alzette, Luxembourg
Small and medium-sized enterprises (SMEs)
  • Pharmacoidea Fejleszto Es Szolgaltato Kft, Szeged, Hungary
Patient organisations
  • Alzheimer Europe, Luxembourg, Luxembourg
Third parties
  • Institut National De La Sante Et De La Recherche Medicale, Paris, France

Participants
NameEU funding in €
Alzheimer Europe99 000
Consorci Institut D'Investigacions Biomediques August Pi I Sunyer340 710
Erasmus Universitair Medisch Centrum Rotterdam314 835
Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V.1 743 513
Fundacio Barcelonabeta Brain Research Center209 778
Gottfried Wilhelm Leibniz Universitaet Hannover276 855
Institut Du Cerveau Et De La Moelle Epiniere1 280 914
Karolinska Institutet876 010
Neurorad SRL (left the project)70 238
Pharmacoidea Fejleszto Es Szolgaltato Kft359 103
Universitatsklinikum Bonn1 172 160
Universite D'Aix Marseille264 357
Universite Du Luxembourg325 355
University College London (left the project)184 011
 
Third parties
NameFunding in €
Institut De Neurosciences Translationnelles De Paris (Ihu-A-Icm) Fondation (left the project)242 395
Institut National De La Sante Et De La Recherche Medicale234 000
 
Total Cost7 993 234