NIHRDataInsights/HRCSData huggingface dataset:
Title: FAP-DMD: Elucidating the role of FAP cells in the process of muscle degeneration in patients with Duchenne muscular dystrophy
Funder: Medical Research Council

Abstract: The process of muscle degeneration in Duchenne muscular dystrophy (DMD) has been extensively studied in mice. In recent years a new type of cell called fibro-adipogenic precursor cell (FAPs) has been discovered. These cells have a pivotal role in both muscle regeneration and degeneration regulating the function of other muscle stem cells and producing fibrotic and fat tissue contributing to muscle fiber lose. Research in murine models have generated candidate molecular targets for therapies although there is still a considerable 'translational gap' between these putative targets and effective therapies for patients. This is in part due to limited definition of the functional heterogeneity and interactome of cell lineages that contribute to the muscle degeneration, which is imperfectly recapitulated by rodent models. We have developed a new protocol to isolate FAPs and other muscle cells from muscle biopsies. We have already identified that there are different subpopulations of FAPs in DMD with a different gene expression profile whose function in completely unknown. We will isolate these subpopulations and study their biological properties and how these cells interact with other muscle resident cells. Additionally, we will study the temporal dynamics of FAP subpopulations through the progression of the disease and the molecular pathways governing changes in their phenotype. These experiments will identify molecular targets for the development of new therapies that could influence FAP cells function. In this sense, we have recently identified a series of drugs that slowed down disease progression in mice. We will test these drugs in the cells obtained from patients to confirm their effectivity in humans as a preliminary step to trials. In summary, we aim to characterize the role of different subpopulations of FAP cells in DMD patients to discover new putative molecular targets for developing new therapies to slow down the progression of this devastating disorder.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: MICA: Combinational therapeutic approaches using regenerative medicine and next generation antivenoms to prevent/treat snakebite-induced muscle damage
Funder: Medical Research Council

Abstract: Snakebite-induced muscle damage is primarily caused by venom metalloproteases and cytotoxic phospholipase A2s (commonly from viper venoms). The currently used antivenoms are ineffective in treating/preventing this condition due to larger IgG molecules and blocked/damaged capillaries along with fibrosis in affected muscle. Hence, surgical procedures are used to perform fasciotomy and debridement, and in severe cases, amputation to remove the affected limb. We developed a unique venom-induced muscle damage (VIMD) model in mice and characterised the severity of damage and established the key underlying molecular mechanisms behind this condition. We determined that the persistent actions of venom toxins continue to damage distinct muscle components and prevent muscle regeneration. We hypothesise that it is possible to induce muscle regeneration during VIMD as all the regeneration phases are active. Hence, we propose to develop combinational therapeutic strategies using regenerative medicine and next generation antivenoms to prevent/treat VIMD. We will determine the impact of orally bioavailable drugs such as marimastat and varespladib along with toxin-specific human single chain/domain monoclonal antibodies to neutralise the actions of venom metalloproteases and phospholipase A2 during VIMD using Russell's viper venom and isolated toxins such as a metalloprotease and phospholipase A2. Similarly, regenerative medicine using secretome of adipose-derived mesenchymal stem cells and releasate from human activated platelets will be used to determine their regenerative capability following VIMD. Based on these results, specific combinational therapeutic approaches will be developed and investigated in VIMD under diverse settings. Overall, this study, for the first time, will develop robust combinational treatment strategies that can be further analysed in pre-clinical and clinical studies to treat/prevent snakebite-induced muscle damage and subsequent permanent disabilities.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Wearable Textile with Integrated Electrotherapy and Sensing for Joint Pain Management
Funder: Medical Research Council

Abstract: Osteoarthritis affects 8.75 million people in the UK with the knee being most commonly affected. Knee osteoarthritis causes pain, decreases quality of life, reduces productivity and increases healthcare costs. Transcutaneous Electrical Nerve Stimulation (TENS) is a non-pharmacological therapy providing pain relief by stimulating sensory nerves to block pain signals and produce the body's natural painkiller endorphins. TENS is recommended by NICE as an adjunct to three core osteoarthritis treatments (access to information, exercise, weight loss). TENS devices often include Electrical Muscle Stimulation (EMS) allowing the user to strengthen muscles. There are, however, a number of issues with existing devices: 1) Both TENS and EMS are delivered using either sticky gel electrodes or basic dry electrodes which are uncomfortable. Gel electrodes require regular replacement, adding cost. 2) No existing TENS machines have sensors allowing users/clinicians to monitor progress, customise treatment, or assess knee function. 3) Current products provide many stimulation programmes but insufficient guidance on which to use, making it difficult for the user to select the best settings/programmes for their needs. We will address these issues by developing a wearable electrotherapy product with three main technical advances: 1) Long-life and comfortable electrodes, covering both the knee joint for TENS pain relief and the thigh to strengthen muscles via EMS, embedded in a discreet and aesthetic garment for everyday use. 2) Sensing yarn hidden in the garment to monitor activities and assess knee function. 3) Assessment tool built into the product to assist patients to choose customised settings. The product will be co-developed with end users, design companies, and manufacturers to ensure widespread adoption, market fit and scalability to volume production. A clinical pilot study will establish efficacy in pain management. A Quality Management System and technical documentation will be developed to demonstrate regulatory compliance.


Research activity codes: 5.3 MEDICAL DEVICES;6.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL
Title: Identification of Novel Drug Targets for Osteoporosis through Characterisation of the Genetic Basis of High Bone Mass
Funder: Medical Research Council

Abstract: Aims and Objectives I aim to determine whether putative HBM mutations identified by the UK HBM WES pipeline represent causative HBM mutations by establishing whether: i. the same mutation is found in other HBM cases ii. individuals with a specific mutation have a characteristic phenotype iii. genes identified to harbour putative HBM mutations are likely to play a functional role in skeletal regulation, and represent useful osteoporosis drug targets iv. putative HBM mutations are directly responsible for the HBM phenotype Methodology i. I will interrogate WES data from three extreme HBM populations in order to screen for (a) the same mutation as seen in the index pedigree, and/or (b) other rare mutations/variants in the same gene. ii. I will assimilate a range of clinical (history, physical examination findings), biochemical (markers of bone turnover and 150 metabolic traits) and radiological (radiographs, DXA, peripheral quantitative computed tomography) data for individuals with putative HBM mutations and their relatives. iii. I will use databases (IMPC, IFMRS, MR-Base) and bioinformatics tools (DEPICT, MAGMA) to perform in silico functional analyses. I will use immunohistochemistry and CRISPR-Cas9 knockout to determine the role of identified genes in skeletal development in transgenic zebrafish reporter models. iv. I will build in silico protein models and predict the effect of putative HBM mutations on protein structure and function. I will use CRISPR-Cas9 to introduce a mutation into the zebrafish genome and characterise skeletal effects using fluorescence microscopy (FM) and micro-computed tomography (mCT). Opportunities Characterising the genetic basis of HBM will enable the identification of novel anabolic drug targets for osteoporosis. This will inform the development of much needed new treatments for osteoporosis to prevent fractures and reduce the significant morbidity and mortality associated with this common condition.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: MUSCULOSKELETAL
Title: MICA: Synovial fibroblast pain pathotypes: A roadmap to understanding and targeting the complexity of patient-reported joint pain in osteoarthritis
Funder: Medical Research Council

Abstract: Current analgesics to treat OA joint pain lack efficacy and are associated with adverse side effects. We have found in knee OA patients that inflammation of the synovial membrane (synovitis) is associated with the pattern of patient-reported pain, and that synovial tissue from sites of pain exhibits a differential phenotype with distinct synovial fibroblast subsets which mediate fibrosis, inflammation and neuronal growth and survival. We hypothesise that the pathotype of these pain-associated fibroblasts promote neuronal growth and sensitization of joint nociceptors and drive joint pain in knee OA patients. To address this, we will collect patient-reported pain data (anatomical pain maps and questionnaires), synovitis pathology (MRI), blood, synovial fluid and synovial tissue biopsies from sites of patient-reported pain and sites no pain from n=82 knee OA patients (41 early OA; 41 end-stage OA) undergoing orthopaedic surgery. We will map the synovium expression and spatial location of fibroblast pain pathotype gene signatures and determine the relationship to patient-reported pain and synovitis. RNAseq and proteomic data from OA patient synovium and fibroblasts from pain/no-pain sites will be integrated and computational network models built of the underlying cellular mechanisms between synovial fibroblasts and neurones to identify and validate pathways and candidate targets that mediate nociceptor activity. Antisense oligonucleotides (ASOs) will be designed to silence candidate genes and their efficacy in modulating the fibroblast pain pathotype and reducing the growth and sensory function of neurons determined. Next, the intra-articular delivery of an ASO into the synovial joint tissues and its analgesic efficacy in an experimental model of OA pain will be evaluated. The integration and curation of these multimodal patient datasets and tissue samples will provide new insights into the cellular mechanisms that mediate inflammatory pain.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Pain Mechanisms in long-Covid
Funder: Medical Research Council

Abstract: About 10% of patients infected with COVID-19 have persistent symptoms (long-COVID) that can last for over a year. These include musculoskeletal pain and fatigue as well as paresthesias (tingling, burning pain) and symptoms of dysautonomia (e.g. breathlessness, chest pain). Our proposal will investigate if small fibre neuropathy (SFN) and autommunity are responsible for these neurological symptoms. We will recruit patients who have A) pain and fatigue, B) fatigue but no pain, C) symptoms resolved after COVID, and D) asymptomatic with no COVID infection. Validated questionnaires will be used to characterise the location, quality and intensity of pain and to identify patients whose pain and symptoms suggest (SFN). A diagnosis of SFN will be ascertained by quantitative sensory testing and by histological analysis of intraepidermal nerve fibre density (IENFD) in skin biopsy samples. In addition, we will assess the presence of dysautonomia by measuring cardiovascular parameters in the laboratory at baseline and under provocative testing. We will assess the impact of pain on physical activity during daily life using wearable sensors which capture movement, posture and autonomic data. Blood will be collected from patients for antibody studies. IgG from patient blood will be isolated and administered to mice by intraperitoneal injection. Mice will be tested for their sensitivity to mechanical and thermal stimulation before and then daily after antibody administration. Effects on spontaneous activity will also be assessed as this may be affected by pain/fatigue. The presence of SFN in antibody treated mice will be assessed by measurements of skin IENFD. Fatigue will be assessed by performance on treadmill and rotarod tests. These experiments will show if we can passively transfer symptoms of pain from patients to mice. Immunohistochemistry and Western blotting will be used to identify the cellular binding sites and likely epitopes for patient IgG.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Understanding Acrodysostosis type 1 and 2 through a pluripotent stem cell-disease model.
Funder: Medical Research Council

Abstract: Acrodysostosis is a rare disease characterised by short stature and skeletal abnormalities that affects the axial and appendicular skeleton, characteristically presenting with abnormal shortening of the long bones, small fingers and toes and an underdeveloped upper jaw. Acrodysostosis type 1 and 2 are caused by mutations in the type 1 regulatory subunit of cAMP-dependent protein kinase alpha (PRKAR1A) and cAMP-specific phosphodiesterase 4D (PDE4D) respectively. These mutations interfere with response of chondrocytes in the growth plate to growth controlling hormones such as PTHrP. Human induced pluripotent stem cells (hiPSCs) carrying disease causing mutations can be differentiated into growth plate-like cartilage, the template for bone growth, making them ideal for modelling genetic diseases affecting skeleton formation. We will generate mutations in PRKAR1A and in PDE4D, known to cause Acrodysostosis type 1 and 2, in hiPSCs already present in the lab using CRISPR gene editing. Then we will employ our novel hiPSC differentiation protocol with these syngeneic pairs of mutant and non mutant hiPSC lines, to identify pathways driving the pathogenic mechanisms of Acrodysostosis. Using RNAseq and single nuclear RNAseq as well as conventional immuno- and histo-chemistry and appropriate cAMP signaling (CRE) reporter lines produced in this project, we will identify molecular differences between the lines including in response to hormones (e.g. PTHrP). Specifically affected cell cohorts and potential molecular targets for future drug targeting will be identified through our in house bioinformatic pipelines, which may lead to an effective treatment in future.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: AI for automatic vertebral motion tracking of fluoroscopic images
Funder: Medical Research Council

Abstract: Low back pain is the greatest cause of disability and is thought to be largely related to spinal mechanics. However, the world of spinal biomechanics research is some way away from being able to provide detailed patient-specific assessments of the mechanics of spinal linkages that could lead to better treatments. The hurdle to be crossed is the provision of an efficient method for measuring the motion of the vertebral linkages and analysing the outputs from dynamic sequences of specific movements for abnormalities. Prof. Breen and his team have developed such a method using fluoroscopy (low-dose motion X-rays) - and called Quantitative Fluoroscopy (QF). Use of QF in research has seen international growth, largely due to developments in semi-automatic image analysis, enabling processing of large numbers of images and allowing the identification of biomarkers for nonspecific back pain in patients. However, its potential has always been limited by the processing time and limitation to pristine spinal images. This research aims to overcome these barriers. The team led by Prof. Budka will develop a system using AI and Computer Vision techniques for real-time vertebral detection, identification and tracking, using the existing database of individual in vivo vertebral fluoroscopic images compiled by Prof. Breen. Traditional Computer Vision approaches to object detection rely primarily on object appearance and do not explicitly leverage the hierarchical structure of the scene like the part-whole relationships. Exploiting such structure is key in situations where the image quality is poor and the objects themselves are partially or sometimes even fully occluded. The methodologies and algorithms we develop will be applied to the analysis of an independent sample of spinal motion sequences obtained at the Royal Hampshire County Hospital as a check on their robustness and universality of application, and indication of any necessary domain adaptation.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL
Title: Patient-specific closing wedge femoral osteotomy
Funder: Department of Health and Social Care

Abstract: Around 2.9 million individuals (aged 40-65-years) have radiographic knee OA, costing UK society &pound;24 billion annually, with 80% being productivity losses. Total and uni-compartmental knee-replacement (TKR-UKR) is the main surgical treatment, with the current 160,000 annual procedures set to double by 2030. Although effective for older patients, they are not recommended for early-stage knee OA in young (40-65) active individuals due to the risks of early revision being required. Consequently, younger patients are in a treatment-gap, suffering pain and disability but unsuitable for knee replacement. High Tibial osteotomy (HTO) and femoral (closing-wedge) osteotomy offer a knee preserving cost-effective alternative option. However, surgeons are concerned about performing osteotomies due to surgical complexity and variable patient outcomes. In 2021, 3DMP brought to market HTO_TOKA (Tailored-Osteotomy-Knee-Alignment), a High Tibial Osteotomy, combining additive manufacturing (AM) and digital technologies to deliver minimally invasive devices for faster and superior patient outcomes, reducing operating times and associated costs [1]. Surgeons who utilised HTO_TOKA (including in the PASHion CT [2] identified a clinical need for closing-wedge solutions delivering equal benefits. 3DMP proposes to use i4i FAST to prototype and test a closing-wedge osteotomy solution leveraging its TOKA system that could rapidly be brought to market, benefitting patients, surgeons and NHS trusts. Funding would be used to: Develop and test new resin materials for surgical positioning guides in AM technology for closing-wedge surgery (HTO_TOKA uses Titanium) [3]. Integrate the closing-wedge operation into our existing HTO_TOKA workflow. Validate the process for clinical use by incorporating it into our ISO13485_QMS. Patient and surgeons' involvement via Pashion_PPI and steering committee. MHRA registration. I4i_funding de-risks technology development and allows us to work with surgeons, improving the likelihood of adoption and reducing time to market while allowing us to &quot;fail fast&quot; if the resin-based approach cannot provide surgeons with an acceptable, cost-effective surgical solution.


Research activity codes: 6.4 SURGERY
Health categories: MUSCULOSKELETAL
Title: Cadaveric Study of a Novel Shoulder Stabilisation Device
Funder: Department of Health and Social Care

Abstract: Shoulder dislocations commonly affect young active people with an incidence of up to 80 per 100000 each year(1,2). Surgical stabilisation is considered for up to 68% of these patients to stabilise the joint and prevent redislocation (3). This is commonly performed either by repair of capsular ligaments (Bankart repair) or by transferring bone to augment the front of the glenoid/socket (Latarjet), thus creating a bone-block to prevent dislocation(4). For most patients a Bankart repair is done as this is a simple operation with low risk of complications. After a Bankart repair, up to 35% of patients may have another dislocation(5). A Latarjet can reduce the chance of another dislocation to 1%(4,6,7). However, it has a high incidence of complications of up to 30% (8,9). Most surgeons only consider this risk acceptable in selected patients with a high risk of redislocation. These patients either have glenoid bone damage caused by dislocations or other risk factors including young age, competitive contact sports and shoulder laxity. To avoid the complications from a Latarjet, surgeons are increasingly using novel techniques to treat bone loss with minimal evidence. This includes using cadaver bone or bone harvested from the pelvis to create a bone block(10-12). To address the need for a safer way to treat bone loss we have designed a novel implant designed for mass production, manufactured in surgical grade titanium. Proof of concept has been demonstrated by FEA analysis and cadaveric implantation of a prototype. This demonstrated that our implant was easy to implant, had secure primary fixation and avoided the high-risk steps of a Latarjet. We are applying to seek funding for biomechanical cadaveric testing. We hope the funding will enable us to fast track implant development and proceed with future human studies to generate good quality evidence to support its use.


Research activity codes: 5.4 SURGERY
Health categories: MUSCULOSKELETAL