Centres of Excellences in Neurodegeneration7: Announcement of the CoEN 2017 “Pathfinder II” call

Environment

A key element of the partnership is 3U Biomedical Research which is a major initiative between the three organisations focused on translational research to enable advanced treatments of disease. This initiative is founded on many existing successful collaborations, shared facilities and complementary expertise. It brings together the combined expertise of clinicians, scientists and technologists with a focus on certain key disease areas.

As described in more detail below, one area of particular interest is in neurodegenerative and neurological diseases. This represents an opportunity for a highly collaborative additional centre of excellence in neurodegeneration (COEN). In particular, it would link existing, self-sustaining research centres and maximise their complementary skills. The overall scientific and medical context is outlined below, along with an indication of the key researchers and the targeted diseases.

Scientific context

Neurological diseases are common – one billion people are currently affected worldwide. The prevalence of neurological conditions is increasing as our population grows and ages. The WHO report ‘Neurological Conditions: public health challenges’ found that such conditions account for a substantial disease burden worldwide which is greater than that represented by digestive diseases, respiratory conditions and malignant neoplasms. Neurological disorders constitute a greater percentage of the global burden of disease than HIV/Aids (6.3% versus 5%). Deaths from neuro-disorders are an important cause of mortality and constitute 12% of the total globally. Such conditions are also very significant in terms of YLDs (years of healthy life lost as a result of disability) contributing to over 14% of YLDs globally by 2030. Towards this end, the intellectual calibre and basic/clinical research expertise/accomplishments of inter-nationally recognised PIs at three partnering Institutes (DCU, RCSI and NUIM) are being harnessed and consolidated into an inter-disciplinary COEN.

This scientifically valuable, medically- and therapeutically-relevant initiative would bring together three pre-established and internationally-competitive Centres to work in a focused and collaborative manner: Centre for the Study of Neurological Disorders (CSND), RCSI; International Centre for Neurotherapeutics (ICNT), DCU; and Neuroanalytics plus the associated spin-out company, Cerebro, at NUIM. Moreover, accomplished research clinicians at RCSI and specialist neurologists at the Beaumont Hospital will exploit the outcomes of the basic research for medical applications, through early phase clinical trials.

A major goal is to decipher molecular bases for dysfunctional synaptic function in Amyotrophic Lateral Sclerosis (ALS), Dystonias, Multiple Sclerosis (MS), Chronic Pain and Epilepsy. This will entail advancing the specialised technologies in neuro-protective drug development and delivery, established in the Institutions, initially using the animal models already available. Such landmark advances with these functionally-related abnormalities are feasible through cross-utilisation of powerful new approaches and strategies (e.g. targeting of drugs or corrective genes, protein engineering, combinatorial syntheses and automated screening of potential therapeutics). Also, unique access to animal disease models, pertinent clinical materials as well as patients (for trials), and shared use of sophisticated equipment plus specialised facilities available offers great advantages. Collectively, this would provide a critical mass of experts with complementary research interests and strengths to work synergistically in an internationally-competitive and cost-effective fashion, thereby, creating a truly translational biomedical hub of immense scientific, clinical and strategic importance.

Another objective is to expand the existing ‘one-stop’ pipeline for developing neuro-active drugs for novel therapeutics to alleviate MS symptoms of chronic pain at ICNT to the other diseases (ALS, and Epilepsy, etc.) in which several of the collaborators are specialists. This generic platform established, applicable in principle to any drugs emerging from the programme, would encompass elucidation of the basis for each pathology, identification/validation of therapeutic targets, design/construction of candidate drugs, assessment in animal models and clinical evaluation of preparations certified for human use (a realistic step with the GMP facility coming online in the fall at DCU). This consortium would be the first truly complete ‘hub’ in Ireland to not only perform basic science investigations on these debilitating conditions but, also, actually deliver treatments. Such a powerful, multi-disciplinary COEN will create a lucrative niche and prestigious area for the Institutions, with enormous scope to fulfil unmet therapeutic needs. It will be sustainable due to alignment with lucrative pharmaceutical interests, the prior involvement of several industrial partners and substantial long-term funding committed from Irish agencies (SFI, HRB, EI, HEA) and non-exchequer sources.

Focused, consolidated research on three of the main neurodegenerative diseases:

The inter-disciplinary translational biomedical consortium would focus on three major, functionally-related disease areas in which notable research expertise exists within partnering Institutions, with the lead participants having established national/international reputations.

Neuromuscular disorders [Amyotrophic Lateral Sclerosis (ALS) and Dystonias]: Utilisation of angiogenin in treating ALS is progressing well at RCSI and its effectiveness should be improved through neuronal targeting developed in ICNT. Biotherapeutics that act as muscle relaxants by inhibiting SNARE-dependent exocytosis of transmitters [Dolly, Wang, Lawrence (ICNT, DCU); Molloy (Beaumont Hosp.)], and neuronal targeting of therapeutic genes for ALS encoding protective proteins such as angiogenin [Prehn (RCSI), Ovsepian (DCU)]. This beneficial streamlining of inter-related investigations focused on muscle movement defects should hasten progress with translation and commercialisation of improved biotherapeutics for dystonias, which are ready for preparation under GMP when the facility at DCU gets accredited, so early research-scale evaluation in patients at Beaumont can be launched.

Disorders due to imbalanced release of transmitters/mediators (Epilepsy and Chronic pain): Micro RNA drugs for Epilepsy [Henshall (RCSI), Roche, Commins (NUIM)] plus identification of genetic factors influencing its development and treatment [Delanty, Cavalleri (RCSI)]. Novel treatments are being developed for Epilepsy at RCSI and a patent application has been filed on one of these. Again, in due course, the prime candidates can be produced under GMP for research-scale clinical trials by a renowned specialist, Dr. N. Delanty, and clinical colleagues. Optimising targeted, long-acting inhibitors of the neuronal release of pain peptides to persistently relieve chronic pain [Dolly, Wang (ICNT, DCU); O’Kennedy (BDI); Lowry, Finnerty, Bolger (NUIM); Ruttledge (Beaumont and Mater Hosps). With regard to treating chronic pain that is not responsive to non-addictive medications, candidate therapeutics have already proven effective in animal pain models. Their optimisation is underway with funding from Enterprise Ireland, and GMP forms of chosen variants are to be prepared for testing in severe cases of chronic pain, by the collaborating neurologists.

Multiple Sclerosis (MS): This debilitating disease cannot be treated effectively at present so there is a pressing need for a novel approach to develop therapeutics to alleviate its serious symptoms. Loss of the  myelin sheath from neurons underlying this condition culminates in defective axonal conduction, which is reflected in the many signs of MS, particularly muscle weakness. Changes induced as a result of demyelination alter voltage-activated neuronal channels for Na⁺ or K⁺, whose normal functioning is critical for communication between nerves and muscles. Importantly, analysis of brain autopsies from MS patients revealed a unique oligomeric subtype of K⁺ channel in the demyelinated axons that was absent from the normal samples. Recently, this MS-associated channel was shown to occur at an increased level in the para-nodal regions of demyelinated optic nerve, rather than near the nodes of Ranvier, in an animal model of MS-like condition. As peptide toxin inhibitors selective for the MS channel were shown to restore near-normal conduction in the demyelinated nerves, it is now fully warranted to obtain a non-toxic blocker. This task is being aided by the availability of a recombinant form of the MS channel which has been successfully expressed in a functional form on the surface of mammalian cultured cells. A high priority needs to be given to using the available HTS platform to screen banks of K⁺ channel inhibitors, licensed from pharmaceutical companies. Also, in-house efforts have been initiated to use a chemi-informatic approach to design and synthesise an appropriate inhibitor (Dolly, Al-Sabi, Nolan, Kaza, DCU).

Sustainability and growth of this COEN: The future development of the prioritised core projects is ensured by everyone of the prime PIs being permanent employees with commendable profiles in terms of numbers of papers in high-impact journals, having sizeable groups and maintaining long-term grants over many years (from SFI, HRB, Industrial contracts). The neuroscientists at RCSI have been very successful in securing major grants, ICNT continues to be virtually self-funding (SFI, EI, and largely from a non-exchequer sponsor, Allergan Inc.) and Neuroanalytics at NUIM attracts good support, including a new EI grant on a project associated with this proposal, and recently spun out a new company, Cerebro. Upon obtaining worthwhile data from collaborative pilot experiments, combined grant applications for larger amounts of funding will be written. For example, FP7 had a programme on ‘Innovative therapeutics and medical interventions’. For longer-term sustainability, we envisage using COEN as a vehicle to win major awards through the newly-announced Welcome Trust/SFI Partnership Programmes or European Research Council schemes. A vision for the future includes highlighting the fact that properly promoted and productive/progressive collaborations will underpin and strengthen the existing ‘One-stop platform for developing Neurotherapeutics’. This would be a truly unique facility in Ireland (and rare in Europe) that should allow the ‘Consortium’ to dramatically move the drugs up the value chain, before licensing or finding a partner for full global development. Moreover, it should prove very attractive to pharmaceutical companies because potential GMP-grade neurotherapeutics could be obtained on an analytical scale and ‘fast-tracked’ to first evaluation in man. As well as being cheaper and more cost-effective, this would reduce the risk for companies before committing to large investments for scale-up. Another potentially lucrative source of revenue includes exploiting one or more of the proprietary therapeutic targets from the partners to secure industrial contracts for high throughput screening (HTS) of drugs, provided by pharmaceutical companies under strictly-enforced confidential agreements, using the robotic automated platforms in the National HTS Facility at DCU, funded by PRTLI 4.

Core Researchers and Research Performance
 
Director: The 3U network will operate with a single Director and this position will rotate through the three institutions. The inaugural Director will be Professor Jochen Prehn of RCSI.

Lead PIs and institutional representatives:

• Jochen Prehn, Professor of Physiology and Head, Dept of Physiology and Medical Physics, Director of Centre for the Study of Neurological Disorders (RCSI).
• Oliver Dolly (DCU), SFI Research Professor of Neurotherapeutics, Scientific Director of PRTLI 4 on ‘Target-driven therapeutics and theranostics’, Founder and Director, International Centre for Neurotherapeutics (ICNT).
• John Lowry, Prof and Head of Chemistry Dept (Maynooth University).

 

Principal Investigators:

RCSI:

• David Henshall, Assoc. Prof. Physiology & Medical Physics
• Gianpiero Cavelleri, Research Lecturer in Epilepsy, Genetics and Pharmacogenetics
• Jochen Prehn, Professor of Physiology
• Dr Tobias Engel, StAR Lecturer
• Dr Niamh Connolly, Lecturer in Physiology
• Dr Simon Furney, StAR Lecturer
• Sally A. Cryan, Research Convenor, School of Pharmacy, Member of Irish Drug Delivery Network
• Marc DeVocelle, Lecturer of Pharmaceutical and Medicinal Chemistry
• Melanie Focking, Lecturer in Psychiatric Neuroscience.

 

Beaumont Hospital:

• Norman Delanty, Consultant Neurologist and Director in Epilepsy Service
• David Cotter, Associate Professor in Psychiatry, Clinical Scientist
• Martin Ruttledge (and Mater), Consultant Neurologist
• Fiona Molloy, Consultant Neurophysiologist.

 

Dublin City University:

• Oliver Dolly, SFI Research Professor of Neurotherapeutics
• Jiafu Wang, Faculty Lecturer, Molecular Biology and Protein Engineering
• Gary Lawrence, Faculty Research Lecturer, Cellular Neurobiology
• Jianghui Meng, SFI-funded Research Fellow, Specialist in exo-endo-cytosis
• Saak Ovsepian, Adjunct Faculty Research Fellow, in collaboration with DZNE, University of Munich Richard O’Kennedy, Professor of Biological Sciences, Deputy Director, Biomedical Diagnostic Institute, Expert on single-chain antibodies
• Kieran Nolan, Lecturer, School of Chemical Sciences.

 

Maynooth University:

• John Lowry, Prof and Head of Chemistry Dept
• Richard Roche
• Sean Commins
• John Findlay, Professor of Biochemistry
• Gemma Kinsella, Medicinal Chemist
• John McGinley, Lecturer in Organic Chemistry
• John Stephens, Lecturer in Organic Chemistry
• Niall Finnerty, Post-Doctoral Fellow (Enterprise Ireland CFTD)
• Fiachra Bolger, Research Fellow (Enterprise Ireland)
• Trinidad Velasco-Torrijos, Lecturer in Pharmaceutical Chemistry.

Please contact individual Principal Investigators

List of Principal Investigators can be found at: http://3u.ie/3u-biomedical/3u-neuroscience-coen/