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Addressing the treatment and care of patients with neurological diseases through research

Research on the diagnosis, treatment and management of patients with brain diseases got a recent boost in the form of the establishment of a translational research centre dedicated to the treatment and care of patients with neurological diseases. Hosted by RCSI and incorporating teams at Trinity College Dublin, Dublin City University, NUI Galway and University College Dublin, the €13.6 million SFI FutureNeuro Research Centre began operations in late 2017. It was officially launched by Minister for Business, Enterprise and Innovation Heather Humphreys on 19 November 2018.

FutureNeuro is focused on translational and applied research on chronic and rare neurological diseases. The underlying objective is to improve our understanding of the causes of neurological disease and translate these into something that can benefit clinicians and their patients. The translational part covers a broad range of ‘technology readiness levels’. In some cases, the technologies are already close to patient or clinical use, in other cases, at the start of preclinical development or proof-of-principle.

Pictured L to R: Prof David Henshall, Professor of Molecular Physiology and Neuroscience at the RCSI and Centre Director for FutureNeuro; Mr Jack Banks, PhD student at the FutureNeuro Centre; Minister for Business, Enterprise and Innovation, Heather Humphreys; and Prof Mark Ferguson, Director General of Science Foundation Ireland

Brain diseases are hugely costly for health and society. It is estimated, for example, that as many as 800,000 people in Ireland live with some form of neurological condition, with a healthcare and societal cost estimated at €3 billion.(i)

Besides the challenges of hospital resources, what comes to mind when we think of the most urgent and unmet needs of patients with neurological conditions? Is there an effective therapy? Which is the right drug for my patient? What is the underlying cause? Will they remain stable or will they worsen?

Advances in genetic sequencing

Research to answer these questions is progressing on multiple fronts and there are strong grounds for optimism in the future. Advances in sequencing technology mean that we can decode a patient’s genome faster and cheaper than ever before. But how do we make sense of it all? We have discovered important new pathways that underlie the patho-mechanisms of brain diseases. But are there targets that we can ‘drug’? Also, we now know that certain molecules made only in the brain end up in the circulation and that by combining neurophysiological (EEG) recordings with brain imaging, we can observe changes in function across brain networks. Are these potential diagnostic biomarkers? Can we forecast symptom onset? Finally, information technology has created electronic healthcare record systems in our hospitals. What is their potential? Can they also help patients manage their conditions, report symptoms and recruit for trials? The patient journey must transform and technology is here to help. Realising the potential and continuing to make progress is critical. 

Currently, the centre’s research focuses on two brain diseases. The first is epilepsy, a common brain disease affecting people of all ages in which patients experience frequent debilitating seizures. The second is motor neurone disease (MND), a fatal neurodegenerative disease that destroys the nerves that control movement and breathing.

A key factor in focusing epilepsy and MND is that Ireland is internationally competitive (and recognised) for research on both diseases, including discoveries of their genetic cause(s), biomarkers, therapy and where e-health technology is already being used for research and clinical care. Both diseases share urgent and unmet need. For example, while we have treatments for epilepsy, they are purely symptomatic and do not change the underlying pathophysiology. Drug-resistance leads to inadequate control in another third of patients. For MND, we essentially have no treatments. We need biomarkers to predict disease risk and prognosis. Another rapidly changing landscape is in the area of information technology. Patients increasingly expect (and deserve) greater awareness of their condition and connectivity to their healthcare providers. Lastly, commercial opportunities exist across these research domains which have been recognised by industry, including indigenous Irish companies.  

FutureNeuro’s research programme has three thematic areas.

1.  The projects focused on diagnosis include research to accelerate the introduction of genomic medicine into clinical practice and discover new causes and biomarkers of brain diseases and develop technologies that can detect them.

2.  Therapeutics projects will focus on disease-modifying treatments, with pre-clinical studies that will investigate whether we can target some of the molecules that have been recently shown to co-ordinate the activity of genes in the brain, in particular non-coding RNAs. Neuroinflammation and the role of endocannabinoids are also a focus. In parallel, studies will explore how to deliver to the target (ie, brain). This poses a considerable barrier for oligonucleotide- and gene therapy-based approaches.

3.  The centre’s e-health-enabled research will focus on adapting existing national electronic patient records and registries to record and interpret complex genetic and biomarker data, which can help stratify patients for precision therapeutics. The use of genomics to support the molecular diagnosis for patients with severe epilepsies is already a reality in the centre. In the home setting, mobile devices and apps that allow patients to co-author their medical records will to enrich the clinical record and support more accurate treatment. Remote interaction between the patient and their clinician is an achievable and significant societal benefit.

The centre also aims to provide a broader support for the clinical network in Ireland, resourcing and engaging with a nationwide clinical network, enabling larger-scale research and clinical trial-readiness.

Based on these three research areas, the outcomes anticipated from the centre’s research activities include:

Improved understanding of the basic mechanisms of diseases, such as epilepsy and MND.

Acceleration of precision medicine into clinical practice whereby a patient’s genetic code informs a doctor’s choice of treatment.

Point-of-care diagnostic technology in hospitals and clinics.

Use of e-health technology specifically designed for neurological conditions, coupled with the introduction of genomic information into health records to support better clinical care

New models to screen for disease-modifying treatments.

The development of new medicines that work by targeting previously unreachable genes and companion nanotechnology solutions to deliver them to the affected brain region.

First year in review

The FutureNeuro Research Centre has been operating for just over 12 months. A lot has happened in that time. Nine PhD-driven research projects are up and running and the centre’s head-count has reached nearly 50. Progress has come across all three thematic areas. Genetic studies are pointing to potential predictors of psychosis as an adverse reaction to anti-epileptic drugs. We have established an analytical pipeline for exome sequencing that is facilitating improved molecular diagnosis in the Irish neurology clinic. We are now extending this to genome sequencing in patient-family trios to identify genetic causes of unsolved refractory epilepsy and bio fluid collections are underway to search for nucleic acids and other molecules in blood that might support diagnosis. Adaptation of technology to detect these biomarkers is underway and will eventually be tested in a clinical setting. Work has begun on new models of these two brain diseases, with a specific focus on human neuron models based on reprogramming skin (fibroblasts). Among the therapeutics projects, researchers have tested oligonucleotide inhibitors of non-coding RNAs (part of the genome’s ‘dark matter’) and found promising anti-seizure effects in preclinical models and research is looking at how the blood-brain barrier can be bypassed to deliver these to the brain. Another nucleic acid species has been discovered that rises in the blood ahead of a seizure, suggesting that seizure forecasting may one day be possible. We are also investigating how the brain’s endocannabinoid system responds to seizures and testing the effects of cannabinoids, a recently-approved medicine for intractable epilepsy. Finally, in e-health we are developing new electronic patient records and applying machine and deep learning to clinical data to develop decision support systems.

Four collaborative industry projects have been signed and are underway. These include development of genomic software for epilepsy diagnosis, two pre-clinical projects that will assess effects of novel therapeutics on epilepsy development and an e-health project that will allow patients to monitor their symptoms and query medications using an Alexa-style voice-activated system.

The centre is fortunate to have a strong operations team and centre manager. This team supports biosample collection, business development, grant-writing and education and outreach activities.

Although still early days, research findings have already been published. This includes the discovery that a set of nucleic acids are released from the brain into the blood of patients with epilepsy and the development of a prototype test that could be a useful addition to EEG, MRI and other clinical assessments.(ii)

Year two and beyond

The priorities for year two will be to launch the next set of projects, which include materials chemistry and computer science projects and initiation of further industry projects. We have ambitions for growth, which will include expansion of research projects on epilepsy and MND but in year two we aim to move into other neurological disease areas where the centre’s unique focus can best be applied. We are actively scoping a suite of projects in multiple sclerosis (MS) following the Centre themes, with a possible specific focus on underlying repair mechanisms of MS, new objective measurements of neurodegeneration and the development of an electronic patient register to support remote monitoring and inform further research. It is an exciting time, and we in the FutureNeuro centre are poised to make an impact.     

FutureNeuro is funded by Science Foundation Ireland (SFI) and is one of 17 research centres now operating across science and technology fields. These are the flagship funding instruments for SFI — they provide large-scale, long-term support for basic and applied research that is strategically important for Ireland’s economy and where there is also significant potential for societal impact. Centres bring together world-class multidisciplinary teams to create critical mass in specific areas of research. A major part of the research activities of the centres features partnerships with industry, ranging from small and medium enterprises, to large multinational companies.

References

(i)  https://www.nai.ie/assets/25/0425F95F-FE1F-4D25-BE47D8C6D75756C2_document/IBC_position_paper_final_for_print_March2017.pdf.

(ii)  https://www.ncbi.nlm.nih.gov/pubmed/30396857.

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