NIHRDataInsights/HRCSData huggingface dataset:
Title: Development of a Translational Strategy to Overcome Muscle Paralysis Using Stem Cell Derived Neural Grafts and Optogenetics
Funder: Engineering and Physical Sciences Research Council

Abstract: This project aims to develop our novel strategy to restore lost motor function, using a combination of stem cell-derived neural replacement of lost or damaged motor neurons and optogenetic stimulation to restore control of muscle function. We have previously demonstrated the feasibility of using peripherally grafted mouse embryonic stem cell-derived (mESC) motor neurons that have been optogenetically modified, to restore function to paralysed muscles, using optical stimulation. This approach has significant advantages over conventional approaches to overcome paralysis that typically involve electrical stimulation: i) the neural graft can be specifically and physiologically controlled using light, thus avoiding painful activation of sensory afferents and rapid muscle fatigue; ii) this approach does not depend on the survival of endogenous axons, as the grafted neurons grow to reinnervate target muscles following degeneration or damage to motor neuron axons. A key objective of this study is to pave the way for the essential translational transition from proof-of-concept stage, using mESCs in murine injury and disease models, towards pre-clinical development that will provide an efficient method for safely modifying human induced pluripotent stem cells (iPSCs) and demonstrate the ability of iPSC-derived motor neurons to reinnervate flexor and extensor muscles in the forelimb of adult rats. In principle, the complexity of the motor function that can be artificially controlled using this strategy is limited only by the sophistication of the optical stimulation device. Moreover, coupling of this strategy with brain-computer interface technology would enable the restoration of autonomous control of complex motor functions in a diverse range of patients affected by paralysis. In summary, this strategy enables the bypassing of motor signal blockade that causes paralysis, irrespective of the cause, thus providing a novel therapeutic route to restore lost motor function.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: MICA: MRC Centre for Neuromuscular Diseases
Funder: Medical Research Council

Abstract: The Centre mission is to translate science into experimental medicine & new treatments for children & adults with neuromuscular diseases. We will: 1. Deliver new experimental medicine studies with clinical impact. 2. Develop the core activities/resources that underpin translation including stratified cohorts, MRI biomarkers, neuromuscular biobank, preclinical models & capacity building PhD translational research training programmes. 3. Add value to major programmes of separately funded (>£60m) Centre PI discovery science. Specific technical objectives for the Centre: 1. New experimental therapies: we will deliver a new experimental therapy study in each of five target diseases (muscular dystrophy, channelopathy, neuropathy, inclusion body myositis & mitochondrial disease). 2. Antisense therapy: we will target other dystrophin gene exons using different antisense chemistries & identify new disease targets. 3. Stem cell therapies: we will develop strategies to correct autologous DMD stem cells with a lentiviral vector & assess safety & efficacy using myogenic stem cells injected into a single human muscle. We will develop a safe efficient method to transduce stem cells for systemic delivery. 4. Exercise therapy: we will address key experimental questions in relation to the molecular basis of exercise benefit. We will asses safety & efficacy of exercise in dystrophy, inclusion body myositis, mitochondrial disease & neuropathy. 5. Discover new genes: we will use whole exome next generation DNA sequencing to identify new genes & therefore new therapy targets & new biomarkers in the five target diseases. 6. Industry partnerships: we will build on & add additional successful industry links to 1) develop new experimental therapies eg new antisense chemistries 2) reprofile licensed drugs eg retigabine in muscle channelopathies & bezafibrate in mitochondrial disease and 3) use industry drug libraries to screen animal / biobank cell preclinical models.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Disease mechanisms and therapy for inherited disorders of the neuromuscular synapse.
Funder: Medical Research Council

Abstract: Congenital myasthenic syndromes (CMS) stem from genetic defects that affect signal transmission at the neuromuscular synapse. They provide a rare example of genetic muscle disorders that are treatable if the underlying molecular mechanisms are understood. At least 19 causative genes have been uncovered with mutations identified in proteins involved in signal transfer, synaptic stability, or glycosylation. There are four objectives to this proposal: i) to use next generation sequencing techniques to resolve the genetics behind our residual undefined CMS cases; ii) to find out the mechanisms through which glycosylation mutations impair neuromuscular transmission; iii) to study molecular mechanism to explain how treatment with beta2-adrenergic receptor (beta2-ADR) agonists results in dramatic clinical improvement; iv) when over-expressed in muscle DOK7 generates correctly located but greatly enlarged neuromuscular junctions or 'super synapses'. We will test the potential of these 'super synapses' as a novel gene therapy. Within the laboratory there is expertise for the analysis of neuromuscular junction proteins. Next generation sequencing techniques will be used to screen for genes with new CMS-causing mutations. Molecular genetic (including CRISPR/Cas9 genome editing), biochemical and fluorescence microscopy techniques will be used to generate and study disease models in fibroblast or muscle cells. Effects of beta2-ADR agonists will be studied in transgenic models, in myotube cultures, and within AChR clusters. Detailed analysis of molecular dynamics within AChR clusters will use super-resolution microscopy in combination with temporal and spatial optogenetic stimulation. Therapy, including adeno-associated virus delivery of DOK7 to generate 'super synapses', will be given to transgenic mouse disease models and analysed in vivo by strength tests and electromyography and ex vivo by electrophysiology, microscopy, and biochemical analysis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Sensory system abnormalities in childhood dystonia / dystonic cerebral palsy - are sensory networks modulated by Deep Brain Stimulation?
Funder: Medical Research Council

Abstract: Background: Dystonia can be treated with Deep Brain Stimulation (DBS) of the Globus pallidus interna but outcomes vary widely. My work shows clear differences in neurophysiological parameters between different types of dystonia and suggests these measures may relate to outcome. Aims/Objectives: To compare changes in sensorimotor cortex EEG activity in relation to a sensory or sensorimotor task in children with different types of dystonia and to investigate whether such changes relate to DBS outcome. Subjects: 24 children with primary dystonia, 24 with dystonic cerebral palsy and 24 typically developing children. Methods: Spectral EEG changes will be assessed in relation to a) electrical stimulation of the median nerve as per standard clinical Somatosensory Evoked Potentials, b) a passive wrist flexion/extension task, c) where possible, an active wrist flexion/extension task. Scalp EEG will be recorded using Ag/AgCl electrodes positioned according to the 10-20 system. EEG will be band-pass filtered (1-100Hz), EEG spectral power will be calculated using the Fast Fourier transform or Wavelets, and changes in spectral power, EEG-EEG coherence and EEG-EMG coherence will be measured in four frequency bands (theta 4-7Hz, alpha 8-12Hz, beta 13-30Hz, gamma 31-85Hz). Spectral changes will be compared across aetiological groups and in relation to DBS outcome. In children who have had DBS, neural connections between the Globus Pallidus and sensorimotor cortex will be analysed using Deep Brain Stimulation Evoked Potentials. Firing patterns of pallidal neurons will also be assessed using micro-electrode data recorded from the Globus Pallidus at the time of surgery. Scientific and medical opportunities: This work has important implications a) for increasing our scientific understanding of the mechanisms of dystonia and b) for clinical decision-making, by using neurophysiological parameters to predict outcome, thus improving patient selection and counselling of families.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Cell mediated gene therapy for muscular dystrophy: steps towards clinical efficacy.
Funder: Medical Research Council

Abstract: This proposal aims to reach clinical efficacy with stem-cell mediated gene therapy for Muscular Dystrophies (MD). The PI completed a phase I/IIa trial based upon intra-arterial delivery of HLA-matched donor mesoangioblasts (Mabs), vessel-associated myogenic progenitors. Since these cells can cross the vessel wall in the presence of inflammation, they can be evenly distributed to downstream muscles, an essential condition for diffuse forms of MD. The trial was safe but not efficacious (especially in comparison with pre-clinical models) for a number of reasons such as the advanced stage of the disease in older patients, the moderate ability of stem cells to engraft and, consequently the need to produce the wt copy of the mutated gene also for the vast majority of resident cells. To address these issues, we will optimise each step of the transplantation protocol with human Mabs (adhesion to the endothelium, migration, fusion with regenerating fibres and finally over-production of the therapeutic gene product) with a number of in vitro assays that will allow to monitor dynamically and at the single cell level the behaviour of human Mabs. We will test different experimental strategies to enhance each of these processes in a fast and reliable way that will also allow to reduce animal experimentation only to these strategies that will have proven efficacious in vitro. Preliminary evidence indicate that at least binding to the endothelium and amplification of dystrophic production may be increased several fold thus strongly supporting feasibility. If successful, this project will set the basis for a rapid clinical translation of autologous, genetically corrected cells in younger dystrophic patients aiming at arresting or significantly delaying the progress of the disease.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: MRC Strategic Award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases
Funder: Medical Research Council

Abstract: We will train a new group of clinical academic fellows to ultimately benefit patients in each partner LMIC. Fellows will be trained to build a cohort of 15,000 Neuromuscular disease (NMD) patients for deep phenotyping and comprehensive genotyping, we will: (i) Establish an easy to use platform for deep clinical phenotyping and sharing of genome data/results between all project members. We will adopt the pseudo-anonymised, secure and cloud based RD-Connect platform (http://rd-connect.eu/), that uses PhenoTips (https://phenotips.org/) and Human Phenotype Ontology (HPO) (http://human-phenotypeontology.github.io/) terminology. This freely available software platform will be used for each patient/family, entered on secure iPAD locally. This platform allows future collaboration with European and International rare disease initiatives. We will also adopt Open-Clinica for natural history of disease, and later therapeutic trials. This approach ensures cross compatibility with national (GEL, NIHR BioResource) and international efforts (RD-connect). (ii) Establish a common laboratory framework for high quality DNA extraction from blood, logged and stored in the cloud database following guidelines of UK accredited diagnostic laboratories. (iii) Establish common genetic screening platform across laboratories, based on a tiering genetic analysis system hierarchy we developed and tested in the UK. This accounts for the molecular test complexity, number of genes and analysis requirements. (iv) Train fellows in core bioinformatics skills and basic genetic laboratory techniques to ensure an equal skill set in each LMIC. (v) Employ integrated genomic-phenotype cloud based platform for effective interpretation and gene discovery. We will identify known and new disease genes, and assess comparative genetic architecture across 4 continents. This will improve understanding of phenotypic variability, disease progression and disease mechanisms, and build "trial ready" cohorts.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Mechanistic studies of opioid-induced exacerbation of chronic pain responses
Funder: Medical Research Council

Abstract: We will investigate the mechanisms by which prior and continued morphine treatment alters behavioural and neuronal responses to future painful injuries in female rats. Outcomes will contribute to the MRC priority to improve human health. Rats will be treated with morphine for 7 days prior to induction of a model of chronic pain (osteoarthritis or neuropathic pain), behavioural pain responses will be measured until day 14, and then a subset of rats will be used to map changes in peripheral hindpaw-evoked neuronal activity across the spinal dorsal horn (DH), compared to control groups, using a novel multi-electrode array method. This activity map will be used to guide Stochastic Optical Reconstruction Microscopy (STORM) studies, which will measure changes in the abundance of AMPA-type glutamate receptors (AMPA-Rs) at identified sensory fibre terminals, to provide a nanoscale measure of altered synaptic strength associated with morphine-induced facilitation of chronic pain responses. Levels of endogenous opioids and mu-opioid receptor (MOR) desensitisation will be quantified in the DH and brain regions central to descending DH neuromodulation, to probe their potential contributions to morphine-induced exacerbation of chronic pain behaviour. This will be complemented by STORM analysis of MOR internalisation in the spinal terminals of the sensory afferent fibres. In vitro evidence implicates a role of spinal BDNF in morphine-induced changes in nociceptive processing. The effects of sequestering spinal BDNF on morphine treatment-induced facilitation of chronic pain behaviour will be determined, and STORM analysis will determine whether this treatment reverses changes in the abundance of AMPA-Rs and/or MOR internalisation in the DH. Advances in understanding of the role of spinal BDNF will provide the foundational knowledge required for future therapies aimed at normalising spinal pain processing and preventing morphine-induced exacerbation of chronic pain response.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Non-invasive Electrical Stimulation to Augment Human Peripheral Nerve Regeneration in Carpal Tunnel Syndrome
Funder: Medical Research Council

Abstract: Background: Carpal tunnel syndrome (CTS) is an entrapment neuropathy with a prevalence approaching 10%. Despite widespread adoption of decompression surgery, with an annual NHS cost >£46 million, recovery remains incomplete in many patients. Electrical stimulation (ES) has augmented peripheral nerve regeneration in animal and human pilot studies, including in CTS. Current approaches are limited as stimulation is invasive and post-operative, requiring implantation of electrodes under general anaesthesia (GA). Recent evidence has shown that pre-operative stimulation may be superior. Despite being action potential-dependent, electrical responses of human nerves during ES remain unknown. Aims: 1) Optimise a protocol for non-invasive stimulation of the median nerve 2) Explore the feasibility of non-invasive pre-operative electrical stimulation in CTS patients Methodology: I will create a finite element model of the wrist from 7T-MRI data and solve for potentials generated by skin electrodes. In conjunction with a simulated axon model, I will use this model to design a protocol that activates axons throughout the median nerve. I will conduct a randomised, single-centre, single-blind, sham-controlled feasibility trial of non-invasive pre-operative stimulation in CTS patients. I will perform deep clinical phenotyping of patients before and after surgery. We will follow patients for 6 months. Primary outcomes: feasibility data including recruitment and retention. Secondary outcomes: changes in phenotype parameters: patient-reported outcomes on hand function, electrophysiology, quantitative sensory/motor testing and intra-epidermal nerve fibre density in serial skin biopsies. Impact: Non-invasive pre-operative stimulation will accelerate adoption of ES for CTS and other nerve injuries, obviating the need for invasive electrode placement and GA, thus easing clinical integration. Computer modelling approaches will enable optimised protocols for specific injuries.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Harnessing sensorimotor cortical plasticity to improve outcomes in children with dystonia and dystonic cerebral palsy
Funder: Medical Research Council

Abstract: Context: The underlying mechanisms of dystonia are not understood. Abnormal sensorimotor processing is implicated, but rarely studied in children, despite many dystonias having onset in childhood or infancy. Using EEG methods I have shown impaired modulation of sensorimotor cortex mu activity and excessive dynamic 4-7Hz neuronal connectivity in response to proprioceptive stimuli in children with dystonia. Objectives: To investigate 1. whether mu modulation can be enhanced in children with dystonia using EEG biofeedback, and whether this correlates with improved motor control, 2. whether excessive dynamic 4-7Hz connectivity correlates with impaired mu modulation or exaggerated low frequency muscular drive in dystonia, and whether these abnormalities are improved by deep brain stimulation, 3. the developmental profile of these phenomena in healthy infants and those at risk of dystonic cerebral palsy (CP). Methods: Scalp EEG will be recorded during a movement task in children with dystonia, dystonic CP and controls. EEG spectral power will be calculated using continuous wavelet transform. Levels of alpha/mu (8-12Hz) modulation and task performance, with and without real-time feedback of EEG mu activity via a brain computer interface, will be compared and correlated. Dynamic connectivity between cortical regions will be investigated using wavelet transform coherency, and dynamic causal modelling techniques will be applied to model the sensorimotor network in dystonia. In infants, scalp EEG will be recorded during rest, sensory stimulation and spontaneous movement. Development of mu modulation and stimulus-related connectivity will be compared in healthy infants and those at risk of dystonic CP. Scientific/Medical opportunities: Advance understanding of mechanisms of dystonia in developing brain; Assess potential therapeutic application of mu biofeedback to improve motor control; Define likely windows of opportunity for interventions to optimise neuroplasticity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;NEUROLOGICAL
Title: Silencing musculoskeletal pain: can we target spontaneously active neurons?
Funder: Medical Research Council

Abstract: Musculoskeletal pain conditions are a leading cause of disability and are poorly treated by existing analgesic medications. We know that pain in these conditions can be effectively treated by blocking sensory afferent input in the periphery. This is evidenced, for example, by the acute analgesic effects of local anaesthetic block or by the attenuation of pain following joint replacements in osteoarthritis. However, a non-selective block of all afferent fibres (e.g. via perineural local anaesthetic application) is not viable due to safety concerns. Thus, our proposal will focus on determining which peripheral afferents become sensitised in musculoskeletal pain to facilitate the development of more targeted analgesic treatments. We will focus on spontaneous sensory neuron activity because this has been recorded from nociceptors of individuals living with chronic musculoskeletal pain, as well as in animal models. Our proposal will use cutting-edge optical imaging technologies, which allow the study of spontaneous firing in afferents in models of musculoskeletal pain. We will identify which types of sensory neurons become spontaneously active using a combination of functional, anatomical and genetic strategies. Once we have identified the major subpopulation of neurons where spontaneous activity resides, we will use a chemogenetic strategy to silence this population and will assess impact on pain behaviours. To understand the relationship between spontaneous activity and rodent behaviour in musculoskeletal pain, we will optimise the use of Miniscopes, so that we can record activity from DRG neurons in freely behaving awake animals. Our proposal will reveal which sensory neuron class we should target in order to eliminate spontaneous activity and consequent pain behaviours. This will help refine any analgesic drug development strategies that are currently being developed for the treatment of musculoskeletal pain.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL;NEUROLOGICAL