NIHRDataInsights/HRCSData huggingface dataset:
Title: Over two years to study NHE1 inhibitors to treat Duchenne muscular dystrophy
Funder: Action Medical Research

Abstract: Background _x000D_Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease which causes major disability, affecting young boys from the age of three to five years and eventually leading to death around their late 20s. There is currently no cure for the X-linked recessive condition and available treatment options focus on managing the symptoms, such as non-invasive ventilation at night to aid breathing and use of steroids to aid muscle strength. Despite improved care standards, patients are still losing the ability to walk around 12 to 14 years of age and subsequently dying as a result of heart and lung failure. Therefore, new treatments are urgently needed that slow down disease progression and improve life expectancy and quality of life. These researchers have identified a class of drugs called NHE1 inhibitors, originally developed for the treatment of heart disease, which may have a profound impact on the disease course of DMD. _x000D_The research project_x000D_ The aim of this project is to test the effects of NHE1 inhibitors in laboratory models of DMD in order to provide information which would then enable these drugs to progress towards clinical trials. The researchers will use a prototype NHE1 inhibitor, which has passed initial safety, pharmacology, toxicology, and pharmacokinetics testing in animals. This research is expected to provide proof of pharmacological efficacy in a model of DMD, which besides adding to our understanding of the disease mechanism of DMD, would then enable rapid entrance into clinical testing.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: A prospective study for osteoporotic fracture in children and adolescents with chronic inflammatory and/or disabling conditions
Funder: Department of Health (England)

Abstract: Dual-energy X-ray absorptiometry(DXA) is a significant predictor of fracture in adults. However, the outcome from adult studies is not necessarily transferable to children. Due to the technical limitations of DXA, a child with reduced stature will have reduced measured bone density, regardless of their true volumetric bone density and may be misdiagnosed as being at risk of fracture. Although there have been studies demonstrating low bone density and increased fracture incidence in children, due to the technical limitations of DXA, low bone density may not necessarily be synonymous with increased fracture risk. The aim of this study is to establish, in a prospective manner, whether there is a causal link between body-size related bone density and low trauma fracture in sick children. Successful outcomes would potentially create diagnostic thresholds for fracture risk in sick children and facilitate levels for intervention to reduce their existing and/or lifetime risk of fracture.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL
Title: Advanced antisense oligonucleotide technology for exon skipping in Duchenne muscular dystrophy.
Funder: Department of Health (England)

Abstract: Duchenne muscular dystrophy (DMD) is the most common lethal variant of muscular dystrophy, and affects 1 in every 3500 live male births or 250,000 people world-wide. Recent encouraging clinical trials have used antisense oligonucleotides (AOs) which, like molecular velcros , are able to temporarily repair the mutated DMD gene and restore the lost dystrophin protein to the muscles of DMD patients. However this approach requires repeated administration of the AO drug in order to achieve some repair of the gene in the skeletal muscle; in addition the heart muscle cannot be targeted efficiently with the current AO chemistries. New generation AOs, never tried before in the human, are able to dramatically improve skeletal and cardiac muscle uptake of these molecules in animal models of DMD and significantly improve their therapeutic efficacy. In this study the MDEX Consortium, a world-leading group of preclinical scientists and clinicians based in the UK developing state-of-the-art therapies for neuromuscular disease, in partnership with AVI BioPharma, a pioneering company developing RNA therapeutics, plans to focus on the development and optimisation of a safe new generation AO drug which we intend to administer to a group of 9 patients affected by DMD after appropriate safety studies.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: An automated tool to identify vertebral fractures in various imaging modalities
Funder: Department of Health (England)

Abstract: Unmet Need: Osteoporosis is a condition in which there is too little bone, andleads to affected patients suffering fractures, most commonly in the spine, wrist and hip. These lead to pain and defomity and often death. Osteoporosis affects 1 in 2 women and 1 in 5 men over age 50 years and the treatment of fractures will cost £2 billion in UK by 2020. Vertebral fractures are the mostcommon fractures in osteoporosis, and if present indicate that the patient is at significantly increased risk of future fractures and should be treated. However, over 50% of vertebral fractures are not associated with symptoms and so their presence may not be suspected; and are often not reported if present on various imaging techniques. Technology: We will develop a fully automated computer tool for identifying vertebral fractures on X-ray images, suitable for adoption within the NHS, building on our existing state-of-the-art image analysis methods. We will demonstrate the tool's accuracy when applied in NHS radiology departments. Impact: By identifying subjects with vertebral fractures who would benefit from referral for further assessment for osteoporosis the system should ultimately reduce the number of fractures, including the numbers of potentially fatal hip fractures.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL
Title: Perfecting soft tissue attachment interface to an osseointegrated transdermal implant to deliver a predictable and robust patient outcome.
Funder: Department of Health (England)

Abstract: Traditionally amputees attach their artificial limb using a socket that fits onto the limb stump. Often attachment is cumbersome, uncomfortable and restricts daily activities. In addition, the stump does not effectively transmit load and control movement. This causes tissue problems, which means that patients must frequently visit clinic and sometimes the artificial limb is not used due to discomfort. These long-term problems are a burden on the NHS and reduce amputees' quality of life. The ITAP system uses an implant attached to the bone that projects through the skin, at which point the artificial limb is easily attached. This device transmits load through the skeleton, which is how loads are naturally transferred. The success of the ITAP implant is reliant on the integration of the skin around the implant to create a seal to prevent infection. We have had success with this skin integration and believe we can improve the seal by promoting soft tissue integration using porous titanium. Additive Layer Manufacturing allows the fabrication of 3D porous implants that will increase this integration. The key deliverable is the translation of this technology into an implant that provides patients with an effective solution for the attachment of artificial limbs.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL
Title: Establishing molecular mechanisms of and countermeasures to muscle decline in space
Funder: Biotechnology and Biological Sciences Research Council

Abstract: We have established the worm C. elegans as a model for studying spaceflight and age induced muscle alteration. Like man, worms display decreased myosin and myoD expression in flight as well as altered expression of genes predicted to be controlled by FOXO. We have shown, on Earth, that RNAi against or mutation in some genes encoding adhesome components, that decline in expression in space, result in weaker worms. We have proposed to NASA to determine if worm strength declines in flight and to ESA to determine if insulin and/or adhesome alteration controls altered gene and protein expression in flight; both proposals have been successful and deemed technically feasible with existing spaceflight hardware. Here we ask for funding to support this selected work. We will use our force measurement device in flight to determine if strength declines as predicted; ground controls and a positive control are included. We will use our past gene expression (affymetrix) and protein expression (iTRAQ) methods to analyse gene and protein expression in wild-type, insulin receptor over expressing, FOXO null, altered adhesome mutant, and in wild-type worms treated with a drug predicted to alter adhesome remodelling. Results from these experiments will tell us if past gene and protein expression changes are indeed relevant to altered muscle physiology in flight and also if gene and protein expression changes are due to altered insulin and/or adhesome function in flight. These results will provide clear direction for the international community on the cause of muscle decline in flight and suggest molecularly based strategies for countering this decline. Additionally, as both muscle attachment proteins and insulin signalling decline in ageing humans it is possible that our results may also be relevant to understanding and treating sarcopenia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: MUSCULOSKELETAL
Title: Protein for Life: Towards a Focused Dietary Framework for Healthy Ageing
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The UK is transitioning to an ageing population. By 2039 it is estimated that 43% of the UK population will be aged over 60 (ONS 2015). Ageing well across the life course is a major public health priority. Ageing is associated with sarcopenia (a decline of muscle mass and strength), which can affect physical functioning as well as being a key determinant of quality of life and premature mortality. Sarcopenia is a complex, multi-factorial syndrome caused by a number of contributing processes. One key factor associated with sarcopenia is protein deficiency. Increasing protein intake throughout the life course may help to reduce the rate of muscle decline and the onset of associated health conditions. Furthermore, the benefits of increased protein intake for older adults for promoting muscle mass have led to recommendations that protein intake should be greater than the recommended daily allowance for older adults. While there has been some investigation of the levels of protein intake by age group, there is a lack of understanding of the social, demographic and psychological drivers of food choices surrounding protein intake. This is despite a wide range of evidence demonstrating the importance of these factors in determining broader nutrition behaviours. Examining how the influence of these factors vary by age will also be important for tailoring interventions to encourage healthy ageing at different points of the life course. As such, it is necessary to develop a strong multidisciplinary evidence base to gain a deeper understanding of the drivers of and the barriers to increased protein intake. Only through such an ambitious approach can an effective set of guidelines be developed to inform useful products to promote healthy ageing.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: MUSCULOSKELETAL
Title: Generating durable and resilient repair of cartilage defects using tissue-specific adult stem cells - a systematic, therapeutic approach
Funder: Biotechnology and Biological Sciences Research Council

Abstract: This programme of research has a single, clear objective, to bioengineer mature adult articular cartilage for durable repair of isolated cartilage lesions in patients. Our approach emulates the natural developmental growth of articular cartilage in two fundamental respects; we will use tissue-specific stem cells to generate hyaline cartilage and induce this cartilage to undergo in vitro maturation so that it becomes as stiff and resilient as adult tissue. To generate the hundreds of millions of stem cells needed for tissue engineering cartilage we will use bioreactors and gelatin-based macroporous beads. The phenotypic status, potency and genetic stability of cells will be monitored during the expansion phase. 3D bioprinting will be used to generate biphasic osteochondral constructs. Cells and biomaterials will be deposited as bio-ink in defined structural configurations having pore sizes that maximise soluble oxygen diffusion, waste removal, growth and differentiation of embedded stem cells. Novel bioprinting methods, including the direct use of expanded stem cells on macroporous beads that will reduce handling, minimising the risk of infection and increasing automation of processes, will be tested. Tissue engineered cartilage will be subjected to growth factor-induced in vitro maturation such that it adopts the functional, structural and biochemical properties of adult articular cartilage. Optimisation of the phenotypic change in cartilage constructs will be monitored by gene expression of maturation-specific biomarkers, by biomechanical testing and imaging using atomic force microscopy, and by using Fourier transform infrared spectroscopy and X-ray imaging to quantify changes in collagen density and orientation. We will conduct a controlled trial to assess the efficacy of tissue engineered in vitro matured allograft cartilage in an approved equine preclinical model of cartilage repair.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: SMART STEP - Stepwise Translational Pathway for Smart Material Cell Therapy
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Joint surface defects are disabling and predispose to osteoarthritis, a leading cause of disability for which there is no cure. Cellular products, such as autologous chondrocytes, suffer from high costs of production and sub-optimal consistency of manufacturing due to the individual isolation, in vitro expansion, and quality controls of autologous cells. We intend to form a knowledge and technology framework for the development and preclinical testing of cell-free bioactive devices capable of recruiting chondrogenic stem cells present in the joint and inducing cartilage formation. Such devices will represent off-the-shelf, affordable, life-long biological solutions for joint surface defects and the prevention of post-traumatic osteoarthritis. Novel material technology allows adaptation of the physical characteristics of the biomaterials to interfere with mechanosensitive signalling pathways that influence cell-fate decisions, proliferation and differentiation. In addition, biomaterials will be engineered to expose, in a controlled way, growth factors that will enhance their cartilage formation. Following in vitro screening in chondrogenesis models, such technologies will be tested, for safety and efficacy, in small and then large animal models of joint surface defect (mice and sheep, respectively) as well as on human cells transplanted in a surrogate potency assay for cartilage formation. The effects of inflammation and proteolytic activity of the joint environment will be tested. A robust management and monitoring structure will ensure optimal use of resources and animals, and coordinate a broad variety of expertise, spanning material sciences, cell biology, rheumatology, orthopaedics, tissue engineering, imaging, and clinical trial methodology, and ensure a seamless delivery of the programme. The early involvement of the TSB Cell Therapy Catapult, industrial partners, and the regulatory agencies will facilitate the transition to the clinical phase.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES;5.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL
Title: Investigating the fundamental mechanisms underlying the phenotypic diversity observed in RYR1-associated Malignant Hyperthermia.
Funder: British Journal of Anaesthesia

Abstract: Malignant hyperthermia (MH) is a pharmacogenetic condition resulting in a potentially lethal reaction triggered during general anaesthesia. In susceptible individuals, this rapid hypermetabolic response results from skeletal muscle calcium (Ca2+) dysregulation. The majority of MH predisposing mutations relate to the RYR1 gene encoding the skeletal muscle Ca2+ release channel, ryanodine receptor 1 (RyR1). Gain of function mutations in RYR1 are increasingly associated with a greater risk of several skeletal muscle pathologies including exertional heatstroke, statin-induced myopathy and premature muscle ageing. The mechanisms of the phenotypic diversity associated with such RYR1 variants and hence potential therapeutic approaches, have yet to be established. However, recently multiple pathways have been implicated in the skeletal muscle Ca2+ dysregulation in MH tissue: store operated Ca2+ entry (SOCE), excitation-coupled Ca2+ entry, and a raised resting Ca2+ entry (RCaE). Our hypothesis is that RYR1 variant-specific differences in the influx of extracellular Ca2+ result in a chronic elevation of resting skeletal muscle Ca2+ concentration ([Ca2+]i), but also dictates the magnitude of response to acute stimulation. This elevation in [Ca2+]i is in turn responsible for the observed MH reaction and the non-anaesthetic manifestations of MH susceptibility. I will use several approaches to alter the Ca2+ handling of immortalized myoblasts derived from genotyped MH susceptible and normal patients to determine the following objectives: (i). the molecular mechanisms underlying SOCE in MH, (ii). the contribution of RCaE to resting [Ca2+]i in MH, (iii). the influence of RYR1 genotype on SOCE and RCaE. Identifying the effects of these pathways on Ca2+ regulation in normal and MH tissue will provide a better mechanistic understanding of calcium homeostasis in health, MH and related diseases. This may reveal novel targets for the development new therapies for such conditions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Does genetic background determine predisposition to sarcopenia? - Analysis of UK Biobank data
Funder: Chief Scientist Office, Scotland

Abstract: Aging-related loss of muscle mass and function, known as Sarcopenia, affects around 20% of those aged 70 or over. Sarcopenia curtails health span compromising the ability of the elderly to live independently and leading to frailty and morbidity. Therefore, understanding the underlying causes of Sarcopenia is increasingly important for optimising preventative measures and developing new treatments. This project aims to assess the role of genetic factors in predisposition to Sarcopenia by identifying genes that influence muscle mass and strength in the elderly.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL
Title: Vitamin K Supplementation to reduce falls in older people - a multicentre trial
Funder: Chief Scientist Office, Scotland

Abstract: Vitamin K is involved in a wide range of biological processes, including vascular, bone, neurological and muscle function. Studies in osteoporosis suggest beneficial effects on bone mineral density, and pilot data suggests that vitamin K supplementation may be able to reduce postural sway in older people – a key risk factor for falls. This pilot randomised controlled trial will test the optimum dose (200mcg and 400mcg vs placebo) of vitamin K given for 1 year to improve postural sway in a group of 81 older people at high risk of falls, will test recruitment rates for a large, community-based falls trial, and will collect preliminary data on falls rates to inform the sample size calculation for a full-scale trial. Recruitment will take place across three sample centres to test the generalizability of the recruitment strategy.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Development of a viable ex-vivo human model for pre-clinical testing of regenerative therapies
Funder: Chief Scientist Office, Scotland

Abstract: Osteoarthritis (OA) is the most common joint disease in the world characterised by damage to the articular cartilage (smooth joint lining). Millions of patients suffer from joint pain and disability due to OA. The potential to regrow this damaged articular cartilage of the joint represents a highly desirable ultimate treatment solution. Laboratory studies of several promising treatments designed to repair/regenerate damaged articular cartilage have been limited by the lack of a working human model. The primary aim of this project is to develop a bench-top human model of articular cartilage repair and regeneration as a standard for laboratory testing. The rationale is based on our ‘proof of concept’ research in an animal model that we have already developed at the University of Edinburgh. We believe that human articular cartilage may be kept alive for up to 6 weeks in the laboaratory (using human tissue discarded during hip surgery) and repair/regenerative responses induced outwith the human body. The main advantages of such a model is the ability to test a wide range of OA treatments directly in the human tissue, paving the way for subsequent targeted clinical studies of laboratory proven strategies with the potential to regrow articular cartilage.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Nanoparticle -mediated microRNA Delivery for increased Osteogenesis in a 3D osteoporotic Bone Marrow Model
Funder: Chief Scientist Office, Scotland

Abstract: Osteoporosis (OP) is a disease that affects the quality and density of bone. The underlying cause is due to an altered bone marrow environment, where the resident mesenchymal stem cells (MSCs) tend towards making fat cells rather than bone cells, resulting in ‘fatty marrow’. Current OP treatments focus on stopping bone resorption (break down); in this project, we want to instead focus on encouraging new bone formation from MSCs in OP patient bone marrow. In particular we will (1) identify differentiation profiles for control and OP MSCs in both 2D and 3D culture models (i.e. the bone-making:fat-making potential of both MSC populations), and (2) use our established gold nanoparticle delivery system to target OP MSCs with specific microRNAs, which promote bone formation. Overall, we will thus determine whether we can control OP MSC fate and encourage bone rather than fat formation, which may lead towards a new therapy for OP patients.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL