JPND: Oligomer-Focused Screening and Individualized Therapeutics to target Neurodegenerative Disorders (OligoFIT)

The overall aim of this project is to develop a novel "biosensor" approach to differentiate protein biomarkers that exist as defined small clumps (oligomer subtypes/ species). By evaluating their presence and relative abundance in relation to other species it is hoped to discover potentially unique signatures in particular subsets of diseases collectively known as synucleinopathies (e.g. Parkinson's Disease, Lewy Body Disorders and related diseases). Such information could potentially be used to signpost disease status, making it useful for deciding possible future intervention strategies. We will test these biosensors with well-curated patient samples (first with retrospective samples from a cohort of confirmed cases, then prospective samples from newly diagnosed individuals). In addition to pioneering active immunisation strategies, we can also use our expertise in developing monoclonals with diagnostic qualities for their therapeutic potential. The ultimate hope will be to develop a way to stratify patient subtypes of Lewy body disorders (e.g. Parkinson's, Lewy Body Dementias, etc) by identifying unique targets present in oligomeric subtypes. Through developing novel biosensors that can be rapidly used at point-of-care to support medical diagnosis and enrich clinical notes, potentially providing information on appropriate treatment options. In practice, this project will help improve the ability to screen and understand the significance of physiologically relevant oligomeric subtypes, and the part they play in the increasingly appreciated complexities of neurodegenerative disease. Thereby providing a rationale for personalised immunotherapeutic or alternative oligomer-specific targeting interventions that can be offered to those most likely to benefit.

Neurodegenerative disorders (NDs) are commonly associated with neuropathologically distinct amyloid plaques, neurofibrillary tangles, intracellular inclusions in the brain. 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. However, explaining the diversity of disease sub-classifications associated with each proteopathic protein is challenging. Recent findings have shown that oligomers possess a heterogeneity of forms, adopting different conformations, interacting with other proteopathic partners and are likely the result of a 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.
The existence of distinct strains of aggregates or combinations of aggregates may be indicative of disease subtype, stage and confer some prognostic value. Utilising a coordinated multifaceted approach, we will study oligomers (representing pathologically relevant species) and generate a panel of oligomer specific mAb binders (screening out monomer and fibril interactors). The project will further explore differences between physiological and experimental aggregate intermediates and test these in established and novel aggregation and seeding assays to determine behaviour and neurotoxicity. Innovative biosensors based on individual or multiple panels of interactors will be produced and tested with peripheral patient samples (e.g. cerebrospinal fluid and sera). Providing a unique opportunity to investigate differences in oligomers from different synucleinopathies as a strategy to inform the design of targeted immunotherapies, that can be personalized to match the individuals' unique biomarker signatures.

Principal early beneficiaries of this project will be researchers with an interest in neurodegenerative diseases, including neuroscientists, cellular and molecular biologists, biochemists, biomedical engineers and research clinicians. Ultimately, discoveries and translation of research findings will benefit patients, their families/ carers, and clinicians, as well as a broader society to help provide insight and treatment options for managing neurodegenerative disorders.

The main aims of this project are to detect pathological oligomer components with relevance to disease severity/ status. Based on a working hypothesis that the existence of co-oligomer and co-aggregate species may better characterize diseases. The main Research Questions are: Can a rapid biosensor-based assay differentiate between pathological substrates and are these capable to stratify disease class/ status? If so, can we selectively target proteopathic species combinations for personalized medicine? Answering these questions will provide insight into related pathologies and increase confidence in the development of tailored immunotherapies (such as therapeutic vaccines simultaneously targeting multiple oligomers).

A long-term view will look to further refine and improve the design and utility of biosensors for real-world use ahead of formal trials. A preferred embodiment would be to create a prototype that can be readily paired with smart devices and databases to train neural networks for AI. Where appropriate Patents will be filed following the advice of knowledge transfer experts at the necessary stage to protect potential interests enabling future investment, securing a route to market for novel products in the long-term.

Also, successful vaccine candidates will need to be robustly tested preclinically before they may be advanced to the clinical trials. However, an extensive preclinical package, including a sound understanding of the exact oligomer-type recognized by the antibodies induced by vaccination will be of great help to secure interest in funding cGMP production and subsequent clinical testing of vaccine candidates/ biological immunodrugs generated in this proposal.

We expect to play our part in supporting a well-informed and empowered patient population. With the hope to involve them further as stakeholders and provide opportunities for exchange with broader research communities. Furthermore, we will actively seek interactions with policymakers at all levels of government as well as non-government organisations (industry and charities) contributing to efforts in raising the profile of neurosciences and neurodegenerative research. Where possible (and appropriate) helping to provide evidence for prioritising support for these areas.

Ultimately we hope the primary beneficiaries of this project are patients affected by synucleinopathies and their families. By empowering clinicians and healthcare providers with more tools to diagnose and possibly decide on appropriate therapies for intervention. The wider scientific community, especially with interest on dementia, will find interest in methodologies and research findings of this project. Solutions addressing ever-growing social and economic burden of dementia globally will help all societies.