NIHRDataInsights/HRCSData huggingface dataset:
Title: Preclinical development of TRPC3 inhibitors for Spinocerebellar Ataxia
Funder: LifeArc

Abstract: Ataxia comes from a Greek word meaning ‘lack of order’ and is a term for a group of disorders that affect movement, balance and speech. These clinical symptoms reduce patients’ quality of life. Sometimes, people suffering from ataxia develop cognitive disabilities and many ataxias lead to premature death. The subgroup of the Spinocerebellar Ataxias (SCA) are inherited neurodegenerative disorders. They are characterised by the loss of specific nerve cells called Purkinje cells in the cerebellum, the part of the brain that controls movement and coordination. There is currently no cure for SCA and patients urgently need new treatment strategies. Although more than 40 gene mutations lead to SCA, it is believed that many genetic forms are caused by common underlying disease mechanisms. Notably, TRPC3 – a transient receptor ion channel that regulates the calcium balance in Purkinje cells – acts abnormally in people with SCA. The team is investigating whether inhibiting TRPC3 could improve outcomes for people with SCA. While there are currently no selective and potent inhibitors of TRPC3, the team identified two hit compounds that act against TRPC3 in a previous collaboration. The funding enables the team to study these compounds to generate drug leads that offer the best prospects for inhibiting TRPC3. They will then test those compounds in disease-relevant models with the aim of translating them into a treatment for patients with SCA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Non-invasive MRI of Blood-Cerebrospinal Fluid Barrier Function: A Breakthrough Translational Method to Improve Treatment for Idiopathic Intracranial Hypertension
Funder: LifeArc

Abstract: Idiopathic intracranial hypertension (IIH) is a rare disease that most commonly affects women of childbearing age. Patients experience extremely painful headaches and can suffer loss of vision that, for many, leads to permanent damage to their eyesight. The condition causes fluid pressure to build up in the brain. The primary source of this fluid pressure is a structure in the brain called the choroid plexus. While drugs can control the function of the choroid plexus, research has revealed that the benefits of these drugs are highly unpredictable. This reflects a lack of data measuring how effectively the drugs affect the function of the choroid plexus and the resulting change to brain fluid pressure. The team’s laboratory had previously invented the first non-invasive technique, using MRI, to measure the function of the choroid plexus – the part of the brain that these drugs seek to target. In this study, the team is using the new, non-invasive technique in combination with intra-cranial pressure monitoring techniques to see how a range of drugs already approved for IIH affect choroid plexus function and brain fluid pressure in anaesthetised mice. This will allow the team to define how drugs affect choroid plexus function and brain fluid pressure for the first time. The resulting data will fill a gap in knowledge about the mechanisms that underlie drug treatment strategies for IIH and provide a strong foundation for improving drug treatment for patients. The technique has potential as an enabling technology and further development through this project could enable better drug assessment in other indications linked with raised ICP and ChP dysfunction.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Improving blood brain barrier crossing peptides in lentiviral-mediated stem cell gene therapy for Hunter Syndrome (Mucopolysaccharidosis type II - MPS II)
Funder: LifeArc

Abstract: Hunter syndrome, also called mucopolysaccharidosis type II, is a rare genetic disease that almost always affects boys. Children born with the condition can experience a wide range of symptoms affecting many tissues and organs, including their brain, liver, lungs, bones, eyes, skin and heart. Sadly, their lives will often be cut tragically short. The condition is caused by a faulty gene – called ID2 – that leads to the lack of an enzyme that breaks down complex sugars in the body. As a result, these molecules start to build up in the child’s body, causing a range of problems. Children with the most severe forms of the illness will have progressive learning difficulties and behavioural challenges. There is an urgent need to develop new treatments for boys with this devastating condition – especially those that can reduce brain symptoms. Professor Brian Bigger’s team has previously developed a stem cell gene therapy approach that aims to deliver the missing enzyme into the child’s body. This involves taking stem cells from the bone marrow, inserting a correct copy of the IDS gene, and transplanting them into the body. These cells can then make the IDS enzyme, treating the symptoms of the disease. But unfortunately, the researchers have so far struggled to get high enough levels of the enzyme into the brain, as it is protected by the blood-brain barrier. They have had an impact on brain symptoms by adding a small protein tag that helps the enzyme to cross the blood-brain barrier. Building on these encouraging results, the team is now testing several other tags to find out if they can further boost the levels of the enzyme in the brain and other organs. If this laboratory research shows this innovative stem gene therapy is safe and effective, it could pave the way for a future clinical trial in boys with Hunter syndrome.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Developing small molecule inhibitors for a rare childhood seizure disorder, Pyridoxine-Dependent Epilepsy (PDE)
Funder: LifeArc

Abstract: Pyridoxine dependent epilepsy (PDE) causes frequent seizures that begin soon after birth or during infancy. A faulty enzyme, ALDH7A1, is unable to play its usual role of breaking down an amino acid called lysine. As a result, toxic chemicals build up in the child’s body. These chemical imbalances lead to seizures and – in some children – delayed development and learning disabilities. Current treatment focusses on seizure control but does not address the long-term neurological and cognitive causes. Led by Professor Wyatt Yue, the team aims to develop a therapy that reduces the build-up of the toxic chemicals in the body. Professor Yue and his colleagues hope to achieve that by reducing the activity of another enzyme also involved in lysine break-down, an approach known as substrate reduction therapy. The approach has been successfully applied to other rare diseases. The team are making tiny changes to the chemical structures of several potential drug compounds they have already identified. They will then test the effects of the most promising drug candidates in cell studies, selecting the best ones for potential future development into treatments for patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: A Phase II Study of a Novel Vitamin Metabolite (CoA-Z) for Pantothenate Kinase Associated Neurodegeneration (PKAN)
Funder: LifeArc

Abstract: People with pantothenate kinase-associated neurodegeneration (PKAN) experience a progressive degeneration of the nervous system (a neurodegenerative disorder). MRI scanning has also revealed a build-up of iron in the brain. Following normal early neurodevelopment, patients increasingly experience problems with their cognitive and physical abilities. Eventually patients are wheelchair-bound, unable to speak and fully dependent for daily living activities. The disease is caused by a mutation in the protein coding gene PANK2, which provides instructions for making an enzyme called pantothenate kinase 2. This enzyme is active in specialised cellular structures called mitochondria, which are the cell’s energy-producing centres. MRI scans show a build-up of iron in parts of the brain. There are currently no treatments that significantly modify the condition. The funding will support UK participation in a Phase 2 safety and tolerability trial of a drug developed by collaborators in the United States that has produced encouraging results in mice. The team’s US partners will conduct a trial with 48 patients. Given the disease rarity, the UK team’s simultaneous trial involving 24 patients will substantially strengthen the study conclusions. The trial will take two years.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: EEG neurofeedback as a treatment method for Parkinson Disease?
Funder: Division for Social Care and Health Research (Wales)

Abstract: Parkinson’s disease (PD) is the second most common degenerative brain disorder. It severely impairs motor functions causing muscle stiffness, shaking of limbs, slowing and even loss of body movements. PD is a major cause for motor disability in elderly people and responsible for high treatment costs. Recently, we have developed a potential new intervention method for patients with Parkinson’s disease (PD), called neurofeedback. Neurofeedback (NF) helps improving motor function in every-day life by enabling patients to train specifically those brain areas that are involved in the control of body movements. In an initial study, NF treatment improved motor symptoms by 37%. Currently, for this technique to work, patients with PD go into an MRI brain scanner and learn to control their brain activity. However, the use of an MRI brain scanner makes this neurofeedback technique expensive (approximately £500 per hour). A further disadvantage of this approach is the low availability of an MRI machine (only large health care centres have MRI machines). In contrast, another technique, called EEG, is much cheaper, widely available, and does not require a trained expert to be present while it is running. Moreover, EEG NF treatment can improve symptoms in other conditions (e.g. in Attention Deficit Hyperactivity Disorder and Epilepsy), making it a highly promising candidate for our research purpose. This study aims to make the benefits of our scientific research on neurofeedback training available to as many PD patients as possible. We will do this by using the EEG-device to implement neurofeedback training of the areas of the brain involved in movement. PD We expect this technique to lead to similar benefits in motor function as our initial MRI based NF study, and that it can be used as a widespread therapeutic tool for PD patients.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: NEUROLOGICAL
Title: Clinical and cost effectiveness of physiotherapy and occupational therapy versus no therapy in mild to moderate Parkinsons disease: a large pragmatic randomised controlled trial (PD REHAB)
Funder: Department of Health (England)

Abstract: The aim of PD REHAB is to evaluate the clinical and cost-effectiveness of NHS occupational therapy (OT) and physiotherapy (PT) in patients with Parkinsons disease (PD) who report limitations in activities of daily living.The trial is a large pragmatic multicentre randomised controlled trial of OT and PT versus no therapy in 750 patients with PD and limitations in activities of daily living from approximately 40 elderly care and neurology units throughout the United Kingdom.PT and OT will be administered in the patients home. The framework for the content of the therapy will be agreed in advance by expert groups based on our previous work on standard NHS OT and the PT Evaluation Project. Therapy will be tailored to the individual patients requirements. Trial therapists will have a spectrum of experience so we will provide an initial training day for therapists as they join the trial to ensure uniformity of practice across the country. Therapists providing the intervention will complete intervention record forms as used in previous complex intervention trials to allow us to monitor intervention delivery. We have successfully piloted some of these forms in the PD OT trial.The primary outcome measure will be instrumental activities of daily living (Nottingham Extended Activities of Daily Living scale) as activities of daily living is the target of the intervention. Secondary outcomes will be: health-related quality of life (Parkinsons Disease Questionnaire 39; EuroQol EQ5D) cost-effectiveness (cost per quality adjusted life year) adverse events and carer quality of life (Short Form 12. Outcomes will be assessed before randomisation and by post at 3 9 and 15 months.


Research activity codes: 6.7 PHYSICAL
Health categories: NEUROLOGICAL
Title: Individual Cognitive Stimulation Therapy for dementia (iCST Trial)
Funder: Department of Health (England)

Abstract: BACKGROUND: Cognitive Stimulation Therapy (CST) as developed by this research group (Spector et al. 2003) is an effective 14 session group programme which improves cognition and quality of life for people with dementia and has been recommended by the NICE dementia guidelines (NICE 2006).DESIGN: Multicentre pragmatic single blind randomised 2 treatment arm (individual CST vs treatment as usual) controlled clinical trial over 26 weeks. The individual CST programme will be based on a modified CST manual the updated CST review and a focus group consultation with people with dementia and their carers. The treatment as usual group (TAU) will not receive any additional intervention. Assessments will be: baseline (pre-CST); 13 weeks and 26 weeks. TARGET POPULATION: People with dementia and their carers in community settings including memory clinics the voluntary sector and day care. HEALTH TECHNOLOGY BEING ASSESSED: Individual CST would be delivered by the family caregiver for 30 minutes 3 times a week over 25 weeks . All sessions will be described in the manual and an accompanying DVD will have other material for each session such as music and visual cues (eg famous faces). Carers will receive a standardised training and receive up to ten hours support including telephone support (initially weekly) and 3 visits. Qualitative interviews will be used to investigate the impact on the carer role and carer relationshipOUTCOMES: Primary outcome cognition and quality of life. Primary economic evaluation: cost-effectiveness analysis from a health and social care perspective and also a societal perspective looking at comprehensive costs. SAMPLE SIZE: This analysis will be based on intention to treat for the primary outcome cognition. A sample size of 260 will have 80% power to detect a SMD of 0.35 using a two group t-test with a 0.05 significance level comparing the individual CST and the TAU groups. Assuming 15% attrition we propose to recruit 306 people with dementia.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: NEUROLOGICAL
Title: Multicentre UK study of the acetylcholinesterase inhibitor donepezil in early dementia associated with Parkinsons disease (MUSTARDD-PD)
Funder: Department of Health (England)

Abstract: A recent systematic review suggested that 24 to 31% of people with PD have dementia (PDD) while from community-based longitudinal studies the cumulative incidence of dementia in PD may be as high as 80%. PDD is associated with increased mortality greater likelihood of hospitalisation and nursing home placement and constrains effective management of the motor features of the disorder. Nearly 90% of people with PDD also experience troublesome neuropsychiatric symptoms with depression apathy anxiety and hallucinations being most frequent. The carers of demented PD patients are more likely to experience higher levels of stress and depression compared to carers of non-demented PD patients.In June 2006 the NICE Guidelines for the Diagnosis and Management of PD recommended further research into the effectiveness and safety of cholinesterase inhibitors in the treatment of PDD. This was identified as a research priority within the guidelines particularly with respect to evaluating efficacy and cost-effectiveness.The objective of this randomised controlled study is to evaluate the clinical and cost-effectiveness of the cholinesterase inhibitor donepezil in the long term management of people with relatively mild dementia associated with Parkinsons disease. The outcomes of this study will inform prescribing policy for the use of these agents in this indication. They will also make a significant contribution to removing uncertainty amongst medical staff the Parkinsons Disease Society as well as users regarding clinical effectiveness and reduce variability in the use of anti-dementia drugs in this context.The total study duration is 60 months. After a 6-month start-up period for site initiation staff appointments and training 500 patients will be recruited from 21 centres in the UK over 24 months (i.e. 24 patients recruited from each centre at a rate of 1 per month). Eligible and consenting participants will be randomised on a 1:1 basis to either donepezil (5mg daily for 8 weeks then 10mg daily) or matching placebo. DeNDRoN will assist with recruitment in these centres. Each participant will receive study medication for a maximum of 24 months. Six months has been allocated for data analysis and writing.MUSTARDD-PD will be conducted by a multidisciplinary team including members of the DeNDRoN Parkinsons disease and Dementia Clinical Study Groups with trial design conduct and analysis via the UK CRC registered Newcastle Clinical Trials Unit.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: A pragmatic randomised controlled trial to evaluate the effectiveness and cost effectiveness of Collaborative cARE for people with DEMentia in primary care (CARE-DEM trial).
Funder: Department of Health (England)

Abstract: A pragmatic randomised controlled trial to evaluate the effectiveness and cost effectiveness of Collaborative cARE for people with DEMentia in primary care (CARE-DEM trial). Primary objective: To evaluate the clinical and cost effectiveness of usual care augmented by collaborative care compared to usual care at reducing behavioural and psychological disorders in people with dementia in primary care. Secondary objectives:1) To develop and pilot the feasibility of a UK model of collaborative care for dementia led by a primary-care based case manager using evidence based care care pathways. 2) To provide a detailed description and analysis of the case management intervention including a description of how it works in practice and a toolkit for its replication should the intervention prove effective. 3) To explore the acceptability and value of a collaborative care model in dementia delivered by a case manager to people with dementia their family carers and other dementia care professionals and services.4) To conduct a cost-utility analysis of usual care augmented by collaborative care management compared to usual care on NHS resource utilisation by people with dementia and their family carers. The outcome in this analysis would be change in quality-adjusted life years (QALYs) derived from the DEMQOL (using an algorithm currently being developed in a study by Banerjee Brazier Knapp and others funded by the HTA).Setting: general practices in North east England London and KentSample size: With the power the study to detect a conservative effect size of 0.4 and an assumed ICC of 0.04 we need to recruit & randomise 54 practices (595 patients recruited 324 patients retained).Method: This project consists of four workpackages:?Workpackage 1: Developing the intervention and customising care pathways from the PREVENT study?Workpackage 2: Pilot (rehearsal) study?Workpackage 3: Main trial?Workpackage 4: Qualitative study extending across workpackages 2 & 3


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL
Title: A Randomised Controlled Trial In Patients With Respiratory Muscle Weakness Due to Motor Neurone Disease of the NeuRx RA/4 Diaphragm Pacing System (DiPALS)
Funder: Department of Health (England)

Abstract: Motor neurone disease (MND) is a devastating illness which leads to muscle weakness and death usually within 2-3 years of symptom onset. Weakness of breathing muscles including the diaphragm (the main breathing muscle) usually results in death in these patients. Non Invasive Ventilation (NIV) therapy is the current standard treatment to help allow these patients to breathe. Patients wear a face mask over their nose or mouth or both. As they breathe in the machine gives an extra push of air to support the patient’s weak breathing muscles enabling a bigger deeper breath. Some MND patients however do not tolerate NIV due to the type of mask they have. During the day problems with using NIV include mask interface problems claustrophobia feeding and communication. Eventually respiratory muscle weakness will progress to a point at which intermittent/overnight NIV is ineffective.Diaphragm pacing (DP) is a means of increasing the strength of the main breathing muscle. The NeuRx RA/4 Diaphragm Pacing System has been developed for patients who are unable to control their diaphragms because of stable high spinal cord injuries or because they have a neuromuscular disease such as MND. The pacing wires are inserted into the diaphragm muscle during a small operation and are connected to a small portable box that the patient can easily carry about. The proposed study will assess if treatment with DP prolongs life and maintains quality of life when given in addition to current standard care with NIV. 108 patients will be recruited to the study in up to 10 NHS sites in the UK. Patients will be randomised to either have NIV or receive DP in addition to NIV. Study participants will be required to complete outcome measures at 5 subsequent follow up time points (2 3 6 9 and 12 months). Patients in the DP group will have additional visits for surgery and a 1 week post operative follow up. 12 patients (and their carers) from the DP group will also be asked to complete 2 qualitative interviews.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: NEUROLOGICAL