Project: Oligomer-Focused screening and Individualized Therapeutics to target Neurodegenerative Disorders

Acronym	OligoFIT (Reference Number: JPND2019-466-136)
Project Topic	Neurodegenerative disorders (NDs) are commonly associated with neuropathologically distinct amyloid plaques, neurofibrillary tangles, intracellular inclusions in the brain. Staging of disease by symptoms has been shown to coincide with a predictable progressive spread of prion-like protein aggregates to different brain regions. The main perpetrators are believed to be small mobile aggregate forms called oligomers, such as a-synuclein (a-syn) in the case of PD, DLB and multiple system atrophy (MSA), so-called Lewy body disorders, that may act as potential biomarkers for those diseases. Oligomers possess the potential to subvert several important pathways and overwhelm cellular functions causing neurotoxicity. In practice it is of course more nuanced, explaining the diversity of disease sub-classifications associated with each proteopathic protein. We recently became aware that oligomers possess heterogeneity of forms, adopting different conformations, interacting with other proteopathic partners and are likely the result of convergence of genetic susceptibilities, lifestyle/environmental factors and ageing. This postulates that disease progression is the result of several factors and as such possibly follows an individualized path for each patient. A critical first step to help decode such patterns is to better understand the composition and identity of particular isoforms in relation to ND status and validate those findings by looking at multiple stages of the same disease as well as other NDs. For this to be possible we need more discriminating tools, and better therapeutics that can selectively target particular subtypes of protagonist oligomer species. We have developed stable, pathologically relevant oligomers, conformational monoclonal antibodies, and vaccine induced antibodies that can recognize toxic intermediates with high specificity. Combining exquisite specificity of antibodies with the sensitivity and high dynamic range capabilities of electrochemical impedance spectroscopy (EIS) we propose to generate oligomer-specific biosensors. We will explore oligomer bioburden in well-characterized patient cohort samples (confirmed and prospective cases versus healthy controls), looking at a combination of samples from the peripheral and central nervous system for correlating biomarker signals and disease status. A particular goal will be to study the presence and consequences of any heterogeneous (co-aggregate) oligomeric entities. Knowledge of the critical epitopes and co- aggregating protein combinations that uniquely associate with particular disease-/ stage-related oligomers, allows for better diagnostics and the rational design of therapeutic vaccines. Our approach will use a novel panel of virus-like particles to generate tailored dual- or multi-specificity responses. We propose to test these vaccines and resulting antibodies for disease-modifying properties (using established in vitro and in vivo models). Eliminating specific pathogenic aggregates and their co-presenting binding partners together may ameliorate specific cellular and proteopathogenic effects, enabling a personalized immunotherapeutic intervention strategy.
Network	JPCOFUND2
Call	PERSONALISED MEDICINE FOR NEURODEGENERATIVE DISEASES

Project partner

Number	Name	Role	Country
1	University of Oxford	Coordinator	United Kingdom
2	University of Warsaw	Partner	Poland
3	University of Aarhus	Partner	Denmark
4	University of Göttingen	Partner	Germany
5	Polytechnique School of Porto	Partner	Portugal
6	Latvian Biomedical Research and Study Centre	Partner	Latvia