NIHRDataInsights/HRCSData huggingface dataset:
Title: From diagnosis to function: the pathophysiological significance of intra-thecal antibody responses to lipids in multiple sclerosis
Funder: Medical Research Scotland

Abstract: Multiple sclerosis (MS) is the most common cause of chronic disability among young adults in the UK and affects over 1 in 500 people in Scotland. However, despite recent advances, the efficacy of current treatments remains limited by factors including large numbers of non-responders and severe adverse effects. Developing prognostic tools to classify patients for treatment, identify those at risk of developing potentially fatal adverse effects and in general, help patients make informed life style changes are now a matter of urgency. Building on previous studies demonstrating MS is associated with lipid-specific autoantibody-responses, we have identified a previously unknown mechanism by which these antibodies act to exacerbate disease activity in Central Nervous System (CNS) inflammation, whilst at the same time reducing their risk of developing a commonly fatal opportunistic viral infection, progressive multifocal leukoencephalopathy (PML). This project will determine which lipid-specificities are responsible for these different biological responses, identify the signalling pathways involved and validate their clinical significance. These studies will lead to the development of new prognostic/diagnostic tools that will improve the clinical management of multiple sclerosis, as well as providing new insights into factors contributing to disease development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Generation and validation of a mouse model of genetic early onset epilepsy and in cage monitoring of seizure activity
Funder: Medical Research Scotland

Abstract: Severe epilepsy is often associated with intellectual disability, and unresponsive to drugs. Genome sequencing has allowed us to identify new genes that are mutated in children, causing their epilepsy. However, if we are ever to be able to come up with new, rationally designed, treatments for these children, we need to be able to model the condition in the lab. We can now use a new efficient way of editing genes to recreate specific epilepsy-causing mutations in mice, but the challenge is to find ways in which we can accurately measure spontaneous seizures in these mice without resorting to induced seizures (a severe procedure which doesn’t accurately reflect the human situation). Actual Analytics have developed a system for monitoring mouse behaviour in their home cages. The student will adapt the system, enabling spontaneous seizures to be monitored with minimal stress to the animals. This baseline information could then ultimately be used to test whether treatments lessen the frequency and severity of seizures. In parallel, the student will look at the effects of the mutations on the proteins found in the nerve cells of the mutant mice compared with their normal littermates, gaining new insights into the biological basis of epilepsy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The ALS Online Genetics Database (ALSoD)
Funder: MND Association

Abstract: The ALS Online Genetics Database, ALSoD, aims to be a continuously updated listing of gene variations associated with ALS, linking to information about how credible it is that any particular gene really is an ALS gene, the clinical features that occur in people carrying specific gene variations, links to other online resources for researchers, and tools that allow ALS researchers to analyze genetic information in detail. There are tools to help genetic counselling and a data sharing system to allow collaboration between researchers who want to access the results of genetic studies. Specific aims within this application to the ALS Association and the MND Association: (1) To maintain an up-to-date list of published ALS genes and gene variants, and continue existing functionality. (2) To develop a user-friendly interface for gene queries able to return published and non-published (database extracted) results. (3) To extract relevant information from existing genetics databases including Project MinE, and the Exome Variant Server, present this as a single unified result. (4) To integrate data from new databases that will be developed as part of Project MinE and other whole genome sequencing projects such as Genomics England and Genome of the Netherlands, so that information from multiple databases can be returned as a single result at a single site. (5) To develop or integrate existing tools for data visualization, data mining and cross-database validation. All development will be done in the context of appropriate feedback from users and Steering Group.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Task force to provide unbiased analysis of Diaphragm Pacing Studies in ALS
Funder: MND Association

Abstract: Weakness of the breathing muscles is a common feature of ALS causing poor quality of life, breathlessness, recurrent chest infections and eventually death. The most effective treatment currently for ALS is a non-invasive ventilator (NIV) that people with ALS (pwALS) use to support their breathing. However NIV can be difficult for individuals to use and even in those that use NIV the weakness progresses and eventually NIV can not compensate. There is therefore a need for additional and alternative options for treating breathing problems in pwALS. Diaphragmatic Pacing (DP) offers such a possibility. A pivotal study in the US demonstrated a survival advantage in people with ALS (pwALS) using DP. The FDA approved DP on humanitarian grounds. The pivotal study compared survival of pwALS using pacing with historical data rather than having a contemporaneous control group. The results from subsequent UK and French studies demonstrated harm in the groups receiving DP compared to contemporaneous control pwALS not receiving DP, Specifically, pwALS who received DP had shortened survival. The aim of this project is to assemble a task force to oversee an independent analysis of all the available data on DP in pwALS to understand the differing results and explore if there are potentially pwALS who may benefit from DP.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: NEUROLOGICAL
Title: Generation and validation of Open Access recombinant monoclonal antibodies for reproducible ALS research
Funder: MND Association

Abstract: We have created a public-private partnership comprising world experts in antibody generation and validation in order to generate, identify and characterize the highest quality, renewable, recombinant antibodies for prioritized ALS-relevant antigens, and to make them freely available to the ALS community. In so doing, we will create a research antibody validation “pipeline” that exploits knock-out cells and mass spectrometry at its core. This pipeline will yield quantitative, standardized and unbiased information about existing and new ALS-relevant antibodies in a range of applications, enabling the community to compare reagents a transparent and quantitiative manner. The project is enabled by the strong commitment of the SGC to open science – all of the research output, reagents, data, and methods will be shared without restriction. This research will yield significant impact in two areas. First, the renewable and recombinant antibodies will enable high quality and reproducible research – laying the foundation for disease understanding and higher quality therapeutic hypotheses for ALS. Second, the team will create a pipeline of antibody validation that will serve the ALS community both now and in the future.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Investigation of TDP-43 misfolding in hiPSC derived Motor Neurons and astrocytes
Funder: MND Association

Abstract: For this study we will use our established and published TDP-43 seeding model and recombinant TDP-43 oligomers in hiPSC-derived MNs and ACs to answer the following questions: (1) Does TDP-43 aggregation in hiPSC-derived MNs and ACs involve other RNA binding proteins known to be associated with stress granules (including TIA, Staufen, G3BP)? (2) Does the formation, spreading and toxicity of TDP-43 aggregates differ between hiPSC-MNs and ACs? If so, by which mechanism(s) in each cell type and could ACs then be targeted therapeutically in ALS? (3) Can we inhibit the formation, spreading and toxicity of TDP-43 aggregates in the cytoplasm through i) relocalising TDP-43 back to the nucleus, ii) enhancing TDP-43 clearance (e.g. activating autophagy) or iii) ‘neutralising’ TDP-43 within the cytoplasm using an antibody? (4) Can hiPSC-ACs confer neuroprotective or deleterious responses to TDP-43 aggregate formation, spreading and toxicity by inducing different states of reactivity (IL6 / TNFa) or quiescence (FGF1)? Answering these key questions will establish whether TDP-43 formation, spreading and toxicity can be ameliorated by targeting TDP-43 protein localization / homeostasis and whether there are hitherto unrecognized cell-type specific characteristics that can be harnessed therapeutically, with focus on astrocytes. This will not only help elucidate pathological mechanisms of ALS, but also provide preliminary targets for therapeutic investigation that would enable the high throughput screening of compounds with tractable and relevant experimental readouts centered on phospho-TDP43 quantitative immunocytochemistry (qICC) and cell death assays.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: A. Kenneth Snowman / MND Association Lectureship in Translational Neuroscience - Liraglutide Extension
Funder: MND Association

Abstract: The objective is to test liraglutide in the SOD1 G93A and TDP-43 Q331K mouse models of MND for both of which we have established readouts and protocols for drug testing. Liraglutide will be tested at a range of concentrations in the SOD1 G93A model. Based on the observed effective dose in the Alzheimer's models of 25nmol/kg, doses of lO fold higher and lower than this will also be evaluated (2.5, 25 and 250nmol/kg) using the 'fastrac' running wheel protocol we have developed to examine effects on early measures of motor system decline. This will also allow us to collect tissue at 60 days and assess the impact of liraglutide on neuromuscular junction innervation as well as inflammatory markers in the CNS (microglial and astrocyte activation), both likely to be influenced by liraglutide treatment. Motor neuron counts will also be performed to assess direct neuroprotection. Samples will also be collected to evaluate liraglutide exposure in plasma and spinal cord at the different doses using ELISA. In addition we will establish the effect of lira glut ide in a TDP-43 Q331K transgenic mouse model of MND recently characterised in the laboratory. In this model we can test a range of parameters including compound muscle action potential (CMAP) with high statistical power using an n of 14 mice per group (Table 1). In this model a single dose ofliraglutide will be evaluated which is based on the known mouse to human translation of the 25nmol/kg dose using FDG-PET. Mice will be assessed up to 6 months of age and tissue then collected for evaluation of motor neuron counts, glial reactivity and NMJ innervation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: A trial of home monitoring for Ventilatory Failure in people living with Motor Neurone Disease
Funder: MND Association

Abstract: This study aims to establish if patients with MND can use a home monitoring device which records expired CO2 and whether this reliably identifies the onset of ventilatory failure (PaCO2 >6kPa). We propose an 18 month proving study with subjects with MND seen in our weekly clinic, divided into an initial 6 month recruitment phase and a 12 month continuation phase. We will invite all patients attending the RSSC with MND and without ventilatory failure to participate. From this cohort (currently around 200 patients) we will identify 30 subjects with preserved bulbar function and measurable respiratory muscle weakness. These subjects would be most likely to get reliable results from the capnometer, be candidates for NIV and to reach one of the study end points within the follow up period. Subjects will be consented for the study and assessed at baseline with arterial blood gas and lung function tests. The majority of subjects will be followed according to our normal routine with 3 monthly appointments. Subjects in the sub group of 30 will, in addition, be given a capnometer to use at home, making measurements morning and evening. All subjects will be followed until they develop ventilatory failure, die or reach 1 year in the study. During the study the results of the capnometer will not be available to the subject or the clinical team managing their care. The primary aim will be to discover whether the device successfully identifies the onset of ventilatory failure (arterial blood gas confirmed PaCO2 > 6kPa) before it is identified through the normal clinical pathway.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Dissecting the contribution of dipeptide repeats to toxicity in C9orf72 iPS-derived neurons from ALS/FTD patients
Funder: MND Association

Abstract: A large (GGGGCC) repeat expansion in the C9orf72 gene is the commonest genetic abnormality in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. There are at least three potential pathomechanisms of neurodegeneration: a) loss of function due to reduced protein expression; b) generation of toxic RNAs that sequester important cellular factors in nuclear RNA foci and c) sense and antisense dipeptides (PR, PA, GR, GP and GA) produced by repeat-associated non-ATG (RAN) translation, that accumulate as intracellular protein aggregates. The relative contribution of these different mechanisms to the development of ALS and FTD remains uncertain. Using induced pluripotent stem cell (iPSC)-derived motor neuron cultures, we have established a range of readouts of cellular toxicity associated with the hexanucleotide expansion (accumulation of RNA foci, altered ER-Ca2+ homeostasis, p62 accumulation, mitochondrial dysfunction and reduced repetitive firing). Moreover, we have recently developed CRISPR/Cas9 corrected C9orf72 lines that do not show RNA foci or RAN dipeptides. This project will analyse the contribution of toxic DPRs to the development of ALS/FTD phenotypes in iPS-derived motor neurons (MNs) and cortical neurons (CNs). We will investigate whether the expression of DPRs in CRISPR/Cas9 corrected MNs and CNs is sufficient to cause toxicity in the absence of RNA foci and characterise the affected cellular pathways. Using pharmacological compounds to dissociate or clear the DPRs formed in the C9orf72 iPS MNs and CNs, we will explore DPR-mediated toxicity as a potential therapeutic target.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Cerliponase alfa for the treatment of neuronal ceroid lipofuscinosis type 2 9CLN2) [ID943]
Funder: Department of Health and Social Care

Abstract: To evaluate the benefits and costs of cerliponase alfa within its licensed indication for treating neuronal ceroid lipofuscinosis type 2 for national commissioning by NHS England.

Lay abstract: Neuronal ceroid lipofuscinosis type 2 (CLN2) is a rare genetic disease caused by the deficiency of an enzyme called tripeptidyl peptidase1 (TPP1). CLN2 is one form of neuronal ceroid lipofuscinosis (NCL), also known as Batten disease. CLN2 disease is inherited as an autosomal recessive disorder, which means that both chromosome copies carry mutations in the CLN2 gene, and both parents are unaffected carriers.1 A deficiency of TPP1 results in abnormal storage of proteins and lipids in neurons and other cells. Accumulation of these proteins and lipids prevent the cells from functioning as they should. CLN2 is characterised clinically by a decline of mental and other capacities, epilepsy, and vision loss through retinal degeneration, and histopathologically by intracellular accumulation of ceroid lipofuscin in the neuronal cells of the brain and retina.2 Symptoms in children with CLN2 start to arise in the second year of life and can then progress rapidly with the onset of seizures, decline in speech, loss of mobility, involuntary muscle spasms and later on, visual impairment leading to blindness. Ultimately the child will become totally dependent on families and carers for all of their needs. Life expectancy is around 6 to 13 years. The exact prevalence and incidence of CLN2 is unknown. It is estimated that in the UK, around 3 to 6 children are diagnosed each year and currently around 30 to 50 children are living with the condition.1 Currently there is no cure or life extending options available. Current clinical management options focus on symptom control, monitoring and prevention of complications, and palliative care. Management aims to maintain function as long as possible and to improve quality of life. This involves a multidisciplinary and multiagency team to control symptoms and complications such as, malnutrition, gastroesophageal reflux, pneumonia, anxiety, Parkinsonian symptoms and dystonia, through medication and physical therapy. Children often receive multiple medications and clinicians need to balance symptom control with the adverse effects and treatment interactions.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Ocrelizumab for treating primary progressive multiple sclerosis [ID938]
Funder: Department of Health and Social Care

Abstract: To appraise the clinical and cost effectiveness of ocrelizumab within its marketing authorisation for treating primary progressive multiple sclerosis.

Lay abstract: Multiple sclerosis is a chronic, neurodegenerative disorder which affects the brain, optic nerves, and spinal cord. It often results in progressive neurological impairment and severe disability. Multiple sclerosis has an unpredictable course with variable severity and progression. Symptoms can include pain, disturbance to muscle tone including weakness or spasticity, chronic fatigue, unsteady gait, speech problems, incontinence, visual disturbance and cognitive impairment. Approximately 90,000 people in England have multiple sclerosis, and about 4,200 people are diagnosed each year.(1) Most people have relapsing-remitting multiple sclerosis, which is characterised by periods of remission (when symptoms are mild or disappear altogether) followed by relapses (which may or may not result in residual disability). Approximately 10% of people are diagnosed with primary progressive multiple sclerosis,(2-4) in which symptoms develop and worsen over time without periods of remission. There are currently no licensed treatments that slow down or stop disease progression in primary progressive multiple sclerosis. NICE clinical guideline 186 recommends ways to manage the symptoms of multiple sclerosis, including pharmacological treatments, physiotherapy and exercise programmes, occupational therapy, cognitive behavioural therapy, fatigue management, and speech therapy. References 1 Multiple Sclerosis Society (January 2016) MS in the UK [accessed February 2016] 2 Multiple Sclerosis Society (January 2016) Types of MS [accessed February 2016] 3 Murray T (2006) Diagnosis and treatment of multiple sclerosis. British Medical Journal 332: 525–7 4 Scolding N, Barnes D, Cader S et al. (2015). Association of British Neurologists: revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis Practical Neurology 0: 1–7

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Ocrelizumab for treating relapsing multiple sclerosis [ID937]
Funder: Department of Health and Social Care

Abstract: To appraise the clinical and cost effectiveness of ocrelizumab within its marketing authorisation for treating relapsing forms of multiple sclerosis.

Lay abstract: Multiple sclerosis is a chronic, neurodegenerative disorder which affects the brain, optic nerves, and spinal cord. It often results in progressive neurological impairment and severe disability. Multiple sclerosis has an unpredictable course with variable severity and progression. Symptoms can include pain, disturbance to muscle tone including weakness or spasticity, chronic fatigue, unsteady gait, speech problems, incontinence, visual disturbance and cognitive impairment. Approximately 90,000 people in England have multiple sclerosis, and about 4,200 people are diagnosed each year.(1) The relapsing form of multiple sclerosis affects approximately 85–90% of people at the time of diagnosis.(2,3) It is characterised by periods of remission (when symptoms are mild or disappear altogether) followed by relapses (which may or may not result in residual disability). Current pharmacological management of multiple sclerosis includes disease- modifying agents to reduce the frequency and severity of relapses and the rate of disease progression. These agents include beta interferon and glatiramer acetate which are not currently recommended by NICE (technology appraisal guidance 32, currently being reviewed), but were available in the NHS through a risk-sharing scheme; this scheme has now ended and a clinical commissioning policy is in place. NICE recommends the following treatment options: • teriflunomide and dimethyl fumarate for active relapsing-remitting multiple sclerosis, only if people do not have highly active or rapidly evolving severe relapsing-remitting multiple sclerosis (technology appraisal guidance 303 and 320 respectively) • alemtuzumab for active relapsing–remitting multiple sclerosis (technology appraisal guidance 312) • fingolimod for highly active relapsing-remitting multiple sclerosis in adults who have an unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with beta interferon (technology appraisal guidance 254) • natalizumab for rapidly-evolving severe relapsing-remitting multiple sclerosis (technology appraisal guidance 127) • daclizumab for active relapsing–remitting multiple sclerosis (including highly active disease) previously treated with disease-modifying therapy, and for rapidly evolving severe relapsing–remitting multiple sclerosis, only if alemtuzumab is contraindicated or otherwise unsuitable (technology appraisal guidance 441). References 1. Multiple Sclerosis Society (2016) MS in the UK [accessed September 2017]. 2. Multiple Sclerosis Society (2016) Types of MS [accessed September 2017]. 3. MS nternational Federation (2016) Types of MS [accessed September 2017].

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL