The cutting edge of basic and translational neurological research

Ms Bridget Doyle and Dr Susan Crawford outline the latest developments at FutureNeuro

FutureNeuro is the Science Foundation Ireland (SFI) Research Centre for Chronic and Rare Neurological Diseases. As we pass the five-year anniversary since our launch, we reflect on the activities of the centre in 2022 to deliver scientific, healthcare, economic, and societal impacts.

Our vision is to enable people with neurological disorders to live independently. Our mission is faster diagnosis, personalised treatments, and patient-centred care.

About FutureNeuro

Hosted by the RCSI University of Medicine and Health Sciences in Dublin, and under the Directorship of Prof David Henshall, Professor of Molecular Physiology and Neuroscience, RCSI, FutureNeuro is built around the vision and excellence of an investigator group based at seven leading universities in Ireland (RCSI, Trinity College Dublin (TCD), Dublin City University, University of Galway, University College Dublin (UCD), University College Cork (UCC), and the Walton Institute). The centre is integrated into specialist neurological care hospitals (primarily Beaumont and St James’s Hospitals in Dublin). This, in partnership with the broader clinical network, and charity and patient organisations, enables access to a research-active clinical network and research-committed patient groups. These support the collection of valuable data and biosamples and the development of patient registers, integrating multi-modal data to drive research questions. A unique element of our R&D programme is the role played by patients and representatives in guiding our research.

Research focus

Since 2017, FutureNeuro has conducted frontier, multidisciplinary translational research on molecular mechanisms, biomarkers of brain diseases and new therapeutic targets, using advanced genome interrogation, systems disease modelling, and clinical data. Our disease approach has been to make scientific advances in epilepsy and amyotrophic lateral sclerosis (ALS/motor neuron disease) that translate into technologies to meet the needs of patients and the health professionals who care for them, and to expand the programme to have impact for other neurological disorders, including multiple sclerosis (MS), psychosis, and paediatric rare disease.

Our research programme focuses on where we are distinct and internationally-leading across our three thematic areas:

Diagnostics: Providing accurate molecular diagnosis through the discovery of genetic and circulating biomarkers of disease and developing technology for their detection.

Therapeutics: Discovery of novel and disease-modifying treatments that target hyperexcitable and damaged brain networks, optimising treatment and clinical trials. Our targets include non-coding RNAs, the blood-brain barrier and neuroinflammatory pathways, and gene therapy, alongside traditional small-molecule approaches to modify those targets.

E-health: Delivery of proactive, personalised and precision patient management and the development of research-enabled healthcare systems and connected health solutions to improve care, enrich research, and facilitate clinical trials.

Examples of FutureNeuro scientific publications in 2022

Under our mission to deliver scientific advancement in neurology, we published over 60 multidisciplinary papers in 2022 covering topics including genomics, biomarker-based diagnostics, new targets for therapeutics, electronic and digital health, and emerging research into the impact of Covid-19. Here is a selection of some recent publications:

Microvascular stabilisation via blood-brain barrier regulation prevents seizure activity Nat Commun. 2022 April

Tight junction proteins provide the molecular glue that ensures the integrity of the blood-brain barrier, a vital structure that separates the brain from the circulation. Claudin-5 is the most enriched of these in the endothelial cells that form the small blood vessels in the brain. Led by Prof Matt Campbell, TCD, researchers discovered that many of the endothelial cells in the brain of patients with drug-resistant epilepsy are lacking claudin-5. Modelling low claudin-5 levels in mice resulted in animals with spontaneous seizures. The team also found a small molecule drug that boosted brain levels of claudin-5 and protected against seizures. The findings could lead to new strategies to treat epilepsy by repairing the blood-brain barrier.

A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam Epilepsia. 2022 June

Levetiracetam (LEV) is an effective anti-seizure medicine, but 10-to-20 per cent of people treated with LEV report psychiatric side-effects, and up to 1 per cent may have psychotic episodes. Research led by Prof Gianpiero Cavalleri, RCSI, sought to determine the contribution of both common and rare genetic variation to LEV-triggered psychiatric and behavioural adverse drug reactions (ADRs). The study identified genetic variation linked to risk of schizophrenia in those who had ADRs to LEV, potentially guiding future physician prescribing decisions.

A clinical decision support system for the prediction of quality-of-life in ALS J Pers Med. 2022 March 10;12(3):435

Prof Catherine Mooney, UCD, and team, in collaboration with Prof Orla Hardiman, TCD and Beaumont Hospital, designed a prototype clinical decision support system (CDSS) to alert clinicians when a person with ALS is experiencing a low quality-of-life (QoL) in order to inform and personalise the support they receive. The CDSS predicts the risk of a low QoL in the form of a probability; a bar plot shows the feature importance for the specific prediction, along with some verbal guidelines on how to interpret the results.

Enhancing arginase-2 expression using target site blockers as a strategy to modulate macrophage phenotype Mol Ther Nucleic Acids. 2022 August

Faults in metabolic pathways are increasingly linked to brain disease. Arginase-2 (Arg2) is a mitochondrially-located enzyme involved in the urea cycle. A previous study by Dr Claire McCoy, RCSI, had found that reduced levels of Arg2 promoted an inflammatory response in macrophages. Now, in their new study led by Ms Jennifer Dowling, RSCI, the team showed they could boost levels of Arg2 in cells by interfering with a microRNA, small non-coding RNAs that dampen gene activity. The team designed and tested a target site blocker (TSB) that cloaks the site where the microRNA usually binds, allowing more of the gene to be made. This strategy could help reduce inflammatory responses in brain diseases including MS.

Social communication skill attainment in babies born during the Covid-19 pandemic Arch Dis Child. 2022 October 11

Co-led by Dr Susan Byrne, RCSI and Children’s Health Ireland, this study reported developmental milestones at 12-month assessment in a cohort of 309 babies born at the onset of the pandemic (CORAL cohort) and 1,629 babies from a historical birth cohort (BASELINE cohort recruited between 2008 and 2011). The study indicated that pandemic-associated social isolation may have impacted on the social communication skills compared with a historical cohort.

Milestones and impact achieved in 2022

The overarching objective of FutureNeuro is to reduce – directly and indirectly – the significant healthcare and societal burden of specific chronic and rare neurological disorders. On the roadmap to achieving this, we aim to build Ireland’s reputation as a location for world-leading neurological research. Key milestones achieved in 2022 and their impact include:

Delivering scientific excellence and research breakthroughs

By the end of 2022, we had surpassed 230 publications, including many in top tier journals: Nature Comms, Brain, Proc Natl Acad Sci USA, and EMBO Molecular Medicine.

FutureNeuro researchers are leading three major EU projects: PD-MitoQuant (mitochondrial dysfunction in Parkinson’s disease); PRIME (synthetic living brain implant to detect and suppress epileptic seizures before they occur); and NeuroInsight (training of 33 research Fellows in neuro and data science).

Through these projects, we are consolidating Ireland’s reputation as an international centre of excellence for brain research

Beginning with €7.9 million in direct funding from SFI in 2017, we have grown to a €33 million national research centre. Recent awards with Queens and Ulster Universities have progressed the shared island research objective.

From an initial application team of 11 principal/funded investigators, the centre has created 106 research and research-support jobs, and is training 32 highly-skilled industry-relevant PhDs.

Increasing international investment in Irish R&D

The research team has successfully competed for non-exchequer funding in excess of €12 million (including Horizon Europe and Wellcome).

We are the go-to research partner for 20+ companies, attracting €3 million industry investment in research across 30 collaborative projects. They range from global pharma (Roche, Novartis, Janssen) to Irish and European SMEs.

Driving improvements in health outcomes, via faster and more accurate genomic diagnosis

Academic and clinic leads (Prof Cavalleri, Prof Hardiman, and Dr Norman Delanty) are playing a leading role to facilitate the clinical implementation of genomic diagnostics in Ireland. To date, researchers have enabled genomic diagnostics for 571 patients, with the goal of targeted treatments and some off-label clinical trials.

Increasing Ireland’s attractiveness as a destination for clinical trials

In 2022, FutureNeuro, along with SFI ADAPT Centre (lead), launched the €9 million multi-modal clinical trials platform for ALS (Precision-ALS), attracting data-centric pharma partners valued at €4 million.

The centre also progressed the development of the Disruptive Technologies Innovation Fund-supported Block-chain and AI Stratified Trials System (BESTS) platform to link patients to clinical trials based on their genomic and clinical data.

Supporting national digital strategy and national genetics and genomic strategy

FutureNeuro is a lead research partner in the €9 million academic-industry Empower data governance programme, leading projects in the areas on safe secondary use of patient data and learning health systems.

FutureNeuro Deputy Director Prof Cavalleri is the joint-lead of the Genomic Data Infrastructure Irish hub. This will position Ireland to participate in the ambitious Europe-wide ‘1+ Million Genomes’ project and support the implementation of the recently-announced National Strategy for Accelerating Genetic and Genomic Medicine in Ireland.

Facilitating patient empowered and remote clinician-patient interaction, via the development of a patient portal for the national electronic epilepsy patient record

This research which was critical during the pandemic era, as it enabled remote clinical interactions, reducing the risk of infectious disease to the 10,000+ epilepsy patients, has been mainstreamed in the post-pandemic neurology clinical care.

Public engagement and public and patient involvement

The past year saw FutureNeuro increase its education and public engagement (EPE) and public and patient involvement (PPI) activities. Researchers engaged with the public, charities, schools, and sports partnerships to grow awareness, inspire and influence change in understanding and knowledge of neurological diseases. This aligns with our vision to create: “A society that is informed about the impact of neurological disease and supports research to address the challenge.”

Researchers combined in-person engagement with schools, both as judges of brain-related initiatives and spoke to students about their research journey, to inspire careers in STEM. The internationally acclaimed ‘Wernicke’s Area’ sound and visual instillation, depicting the story of a woman’s brain tumour and epilepsy hosted at the Irish Museum of Modern Art, resulted from the collaborative initiative of FutureNeuro researcher Prof Mark Cunningham, TCD; and Mr Owen Boss, Artistic Director.

In 2022, we expanded the role of our PPI panel, where people with lived experience of epilepsy, ALS, Parkinson’s disease, and MS review and inform the design of our research programmes. Panel member Ms Colette Daly contributed to the RCSI My Health series together with clinicians Drs Delanty and Susan Byrne and Prof Cavalleri. Our PPI work has in turn shaped the planning of EU activities, including a European workshop on PPI in epilepsy coordinated by the FutureNeuro Director as part of activities with the European Brain Council. To inform the implementation of National Genomics and Genetics strategy, we partnered with IPPOSI and RCSI PPI Ignite, to host a ‘Deliberative Dialogue on Neurogenomics’ where principles of research, policy, and practice in genomic-led research were explored with public patient representatives, researchers, and clinicians.

We launched the ‘Brain Health and Neurology Webinar Series’ with a webinar from Dr Danny Costello, UCC and CUH, to teacher education centres and local sports partnerships. In November, FutureNeuro researcher Dr Omar Mamad, RCSI, organised a very successful CDKL5 fundraising virtual run and joint presentation with Ms Jonna Malone, mother of Mia and CDKL5 Alliance Member. Collaborative initiatives with RTÉ saw highly effective neurogenetic-themed videos circulated via social media for National Science Week.

In 2023, we will expand our EPE initiatives addressing brain health/neurology education to include ongoing webinars, on-site activities, and outreach programmes. Plans are already underway for a Dravet Ireland Event, explorations of the Global Action Plan on Epilepsy, education and public engagement events in conjunction with the International Epilepsy Congress in September 2023, and so much more.

2023 and beyond

During the first six months of 2022, FutureNeuro underwent an intensive evaluation exercise led by an international peer review panel. This included assessing our performance during the first four years across multiple domains – scientific achievement, training, EPE, and the conduct and commercialisation of industry-linked research – and then reviewing our plans for renewal; phase 2 of the centre, which would run from 2023-2029. The phase 2 plans will see an expansion across the current three thematic areas, drawing upon the key discoveries from phase 1, and bringing in additional expertise, technologies, new industry and stakeholder partners.

In terms of scientific direction, we plan to introduce a focus on interceptive medicine and predicting risk and disease trajectory, bridge our genomics and transcriptomics expertise, add neuroelectric biomarkers, digital therapeutics and feedback-controlled gene therapy. Epilepsy and ALS continue as the largest diseases of focus, but we will leverage cross-disease expertise to deliver advances into neuropsychiatric disorders and co-morbid aspects of disease. We plan to incorporate new institutional and national investments in technologies including spatial ‘omics’ and gene therapy to support high-impact mechanistic understanding of therapy and biomarkers and platforms for attracting industry partners.