NIHRDataInsights/HRCSData huggingface dataset:
Title: Active Treatment for Idiopathic Adolescent Scoliosis (ACTIvATeS) – A feasibility study
Funder: Department of Health (England)

Abstract: AIS is a structural lateral curvature of the spine of unknown cause that occurs at ornear the onset of puberty. The effects of AIS include pain cosmetic concernsfunctional limitations cardio-respiratory problems and possible further curveprogression in adulthood. About 10% of AIS cases require surgical or activeconservative management.Current management includes monitoring bracing for some and for the mostprogressive and serious cases surgery. Surgery is a very extensive procedure withexposure of large segments of the spine and substantial fixation which whilst reducingcurve progression also permanently limits mobility in the affected part of the spine.Exercise is a promising intervention for which there is an emerging although lowquality evidence base. The rationale is to use exercises that promote spinal realignmentand hence to either improve or halt progression of the curvature. The aimsof treatment vary somewhat depending on the age of the children as reversibility canbe achieved prior to growth plate fusion but not thereafter. Exercise is potentially alow cost intervention and even if not effective in all it would be of substantial benefit ifthe relative risk reduction in progression to curvature of greater than 45 degrees orrequirement for surgery was reduced in a modest proportion of those participating.The aim is to develop and refine a best evidence exercise intervention ensuring that itcan be delivered within the normal patterns of NHS delivery and to assess the keyparameters needed to finalise the design and project management plan for a definitivemulti-centred randomised controlled trial to evaluate the clinical and cost-effectivenessof scoliosis-specific exercise treatment in AIS in comparison to standard practice.


Research activity codes: 6.7 PHYSICAL
Health categories: MUSCULOSKELETAL
Title: Validation of a novel imaging technique to detect early osteoarthritis using an antibody specific for post-translationally modified collagen type II
Funder: Medical Research Council

Abstract: Given the huge economic and personal burden of OA, there is an urgent unmet need to develop disease modifying OA drugs (DMOAD) that can reduce or stop the progression of the disease. The introduction of potential DMOADs, has so far been hampered by the lack of specific and sensitive serum and/or radiographic biomarkers capable of detecting early disease, and discerning modest changes in disease progression. The development of specific molecular methods for detection of early disease and for assessment of disease response to treatment is an important and tractable area for development in preclinical OA models. Moreover, these techniques can be easily translated for use in human disease. The aim of this proposal is to use an optical imaging technology in conjunction with near-infrared (NIR) fluorescence labeled antibody fragment that is specific to damaged cartilage to visualise the development and progression of murine OA (induced by destabilisation of the medial meniscus (DMM)), and to validate this technique as an early marker for OA. The labelled antibody fragment to modified type II collagen was originally identified from a phage display library and has been used to stain damaged cartilage from both OA and rheumatoid arthritis joints. We have previously shown that it can be used as an in vivo marker of inflammatory arthritis by fluorescently labelling the fragment. We now wish to label the antibody with NIR fluorescence to improve tissue penetration and reduce the problems associated with autofluorescence. We will also modify the fragment by expressing it as a fusion protein, a diabody, to improve signal intensity in the diseased tissue. Ultimately, this targeted approach will be tested in humans with early (cartilage loss on MRI but with preserved joint space on X-Ray) disease.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL
Title: Using Next Generation Sequencing to Unravel the Pathogenesis of Sporadic Inclusion Body Myositis - The International IBM Consortium Genetic Study
Funder: Medical Research Council

Abstract: 1. Library preparation for exome sequencing In each case high quality DNA (A260/280 ratio >1.8) has been extracted. We have switched over to the Illumina TruSeq Enrichment Kit as it allows six samples to be pooled for exome sequencing and is therefore far more cost effective. The enrichment method is a standard protocol from Illumina starting with the TruSeq sample preparation, pooling of six samples, capture of targeted regions with the TruSeq exome kit and then sequencing. The HiSeq has a very large capacity for sequencing, with the TruSeq enrichment our current most cost effective run is 100bp paired-end reads which gives 60 million reads per sample, at around 68 fold coverage (2 samples per lane). Depending on cost we can modify the runs in several ways, usually by extending read length and changing samples per lane. 2. Exome sequence data processing and variant calling After the genome analyser generates the raw sequencing images (image analysis) there are several steps involved in the read conversion to variant calling. These include initial base calling, sequence alignment, building, indexing, sorting SAM files, recalibrating quality scores, removing duplicates and merging lanes. Variants are called and filtered based on quality control (read depth, quality scores etc). A genotype file is produced and then annotation and prediction of consequence (amino-acid change, predicted damage of variant) is carried out using the package Sorting Intolerant From Tolerant (SIFT). 3. Statistical analysis This will primarily focus on gene level comparisons testing a reduced set of genes identified as harbouring non-synonymous coding variants or splice variants that may contribute to risk of IBM. Exome sequence data will be filtered first to remove common variants found in publicly available data from dbSNP and the 1000 Genomes Project. A second level of filtering will be used to extract non-synonymous coding variants and splice variants using existing exome annota


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Intrasynovial soft tissue healing - a novel translational goal for mesenchymal stem cell therapy
Funder: Medical Research Council

Abstract: Rotator cuff tears in humans are common but are still associated with poor outcomes because of their location under compression and within a synovial environment which limits repair. This project tests the hypothesis that the intra-synovial administration of cultured autologous bone marrow or synovial fluid derived mesenchymal stem cells (MSCs) will improve intra-synovial healing of tendons. The project is composed of two complimentary, but not inter-dependent, work packages. The first will establish the relative ability of both two types of MSCs (leading candidates for clinical use derived from bone marrow and synovial fluid/membrane) to augment repair in vitro via two possible mechanisms -engraftment and sealing of the tendon defect to prevent loss of extracellular matrix components which drive synovial inflammation, and their capacity to modulate new matrix synthesis and repair of the defect. The second work package utilises a recently validated, novel, and more highly relevant, cost-effective injury model in a cost-effective large animal (sheep). This model consists of a reproducible surgical defect created tenoscopically in an intra-synovial portion of a tendon that is under compressive load, more analgous to rotator cuff disease than current laboratory animal models of shoulder tendon transection in a quadruped (which are extrasynovial). The use of a large animal enables us to perform autologous injection of MSCs in a manner identical to that proposed for use in humans. This controlled study will compare the effects of treatment with the two types of MSC with saline injection. The data provided in this study will provide in vitro mechanistic data and experimental in vivo verification in a large animal experimental model with similarities to the natural disease in humans to support an application for a Clinical Trials Authorisation for a 'first-in-man' clinical trial planned to dovetail with the end of this project.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: Development of a novel therapeutic for osteoporosis
Funder: Medical Research Council

Abstract: Osteoporosis, which affects a large proportion of the elderly population, frequently results in fragility fractures due to uncontrolled bone loss; 1 in 2 women and 1 in 5 men over the age of 50 will experience an osteoporosis-related fracture during their lifetime. This severely impacts on quality of life and 20-30% of hip fractures lead to death within 12 months. There is currently no ideal treatment for osteoporosis (i.e. due to side effects and problems associated with long-term use, e.g. atypical fractures of the femur and immune suppression) and poor compliance is a significant problem; consequently, treatment rates are less than 20% throughout the world. Most importantly osteoporosis is a long-term condition that requires long-term therapy, i.e. in order to effectively manage the multi-decade "osteoporotic career" of sufferers. Therefore, there is a growing clinical need for the development of new therapies to provide additional treatment options to allow better management of this common, debilitating and potentially fatal disease. We have identified a biologic that is a potent inhibitor of bone loss in vivo, which we propose to develop as a novel treatment for osteoporosis. This drug candidate is derived from a human protein that has a role in the endogenous regulation of bone turnover/remodelling. We anticipate that this recombinant protein domain will have limited undesirable off-target effects (unlike existing therapies), thus enabling its long-term use. This development plan will build on our preliminary efficacy data in order to establish an optimal treatment regime in an FDA-approved model of post-menopausal osteoporosis; initial pharmacokinetic and toxicological testing will also be carried out. This preclinical evaluation will inform and facilitate future studies, including trials in humans, and help us obtain a commercial partner with whom to co-develop our technology.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Controlled release therapeutic coatings for orthopaedic devices based upon novel sol-gel formulations
Funder: Medical Research Council

Abstract: This multidisciplinary project addresses the clinical need to produce a coating system enabling controlled release of antibiotics local to the point of surgery on an optimal timescale to minimise the risk of infection. At the same time the coating may include additional therapeutic agents, such as growth factors to promote osseointegration. This will be achieved by encapsulating single or mixed therapeutic agents within a sol-gel coating. By exploiting the unique property variations (physical and mechanical) of a hybrid sol-gel coating chemistry a new coating will be developed which is specifically designed to counteract the effects of infection arising during implant surgery whilst simultaneously promoting osseointegration between the bone and the implant. The proposed concept is based on a single-layer hybrid sol-gel coating system that contains a depot of active molecules to provide both rapid-activated controlled-release, with zero-release times of less than 15 minutes and sustained release activity of both antibiotic and growth factors up to a period of several weeks. An additional benefit of adopting the sol-gel chemistry route is that, where necessary, it can be tailored to meet the specific clinical need of the individual patient.


Research activity codes: 5.4 SURGERY;5.3 MEDICAL DEVICES
Health categories: MUSCULOSKELETAL
Title: Determining how mutations in myosin cause skeletal muscle disease
Funder: Medical Research Council

Abstract: Laing early onset distal myopathy (MPD1) is a skeletal muscle wasting disease that almost exclusively affects myosin, one of the two main contractile proteins. All the mutations discovered so far are found in the filament forming region of the slow (beta-cardiac) myosin heavy chain isoform. An analysis of these mutations and their positions suggest to us that they are likely to disrupt the structure of the coiled-coil, and this may result in a failure of myosin to incorporate into thick filaments, or it may incorporate less stably and/or disrupt thick filament structure once incorporated into the thick filaments. To investigate this, we plan to use a wide range of approaches to determine how the mutations affect myosin structure, thick filament structure and incorporation of mutant myosins into thick filaments. This will provide a molecular basis for the understanding of this disease that will be crucial for developing future therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: Stem cell metabolomics for bone therapies and tissue engineering
Funder: Medical Research Council

Abstract: The route to meet the objectives is as follows: - Detailed scanning electron microscopy characterisation of natural biomineral surfaces in terms of polymorph (electron backscatter diffraction, EBSD), structure, nano- and micro-topography and crystallographic orientation (EBSD). - Benchmarking the response of MSCs to the well-characterised natural material surfaces above. Cellular response quantified in terms of attachment, spreading and production of markers for formation of bone, cartilage, fat and muscle as well as cell growth and stem cell renewal. - Use mineral-free mimics of nacre and calcite to investigate topographical influence of nacre and calcite and quantify the response of mesenchymal cells to these mineral-free topographies in comparison to the response to natural nacre and calcite. - Quantify cellular response to topography-free nacre and calcite chemistry using XPS in a strategy that isolates mineral chemistry from the chemistry of the intervening organic layers. - Develop techniques to study stem cell differentiation via metabolomics using mass spectrometry and novel bioinformatics. - Quantify metabolomic response to scientist-designed templates (NSQ50 and SQ), natural biominerals and mimics. (Note that the deliberate slight disorder in the nano-pattern of NSQ50 promotes bone formation while the strict order of SQ promotes retention of multipotency). - Produce bio-inspired templates for predictable, tuneable stem cell responses.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: MUSCULOSKELETAL
Title: Targeting WNT/CaMKII in Osteoarthritis
Funder: Medical Research Council

Abstract: WNT signalling drives cartilage loss in osteoarthritis (OA) but could not be targeted therapeutically because it also mediates essential homeostatic mechanism. We discovered that CaMKII mediates WNT-induced chondrocyte dedifferentiation and loss of extracellular matrix production, whereas beta catenin supports chondrocyte proliferation (Nalesso et al. 2011 JCB). New data showed that CaMKII phosphorylation was increased in human and experimental murine OA. Therefore, blocking CaMKII will allow targeting only the pathogenic effects of WNT activation, without affecting its homeostatic functions. Aim 1. To identify the transcriptional signature of WNT/CaMKII activation. To separate CaMKII-dependent from beta catenin-dependent transcriptional targets we will compare (microarrays) gene expression of chondrocytes treated with WNT3A in the presence of either the CaMKII inhibitor KN93 or DKK1 (inhibitor of the beta catenin-dependent pathway) or the inactive compound KN92. Results will be validated by PCR and WB using alternative CaMKII inhibitors. Aim 2. To test whether CaMKII blockade improves experimental OA. OA will be induced by surgical destabilization of the medial meniscus. CaMKII will be inhibited by systemic administration of trifluoperazine or KN93 and cartilage and bone changes will be compared to the respective control groups. Preliminary time course and dose response experiment will be used to fine-tune experimental conditions. Since CaMKII mediates inflammatory pain and allodynia, we will explore if CaMKII blockade improves pain parameters. Aim 3. To identify isoform-specificity/redundancy. Chondrocytes express CaMKII-gamma and -delta. Kinase activity assays following WNT-3A treatment and immunoprecipitation of the 2 isoforms will be used to assess which isoform is activated by WNT3A. Loss of function experiments with siRNA will be used to assess which isoform is responsible for the WNT-3A/CaMKII-dependent chondrocyte de-differentiation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MUSCULOSKELETAL
Title: The role of MMP inhibitors in ameliorating muscular dystrophy
Funder: Medical Research Council

Abstract: Muscular dystrophies are characterised by progressive muscle wasting and fibre loss. This is associated with changes in the composition/organisation of the extracellular matrix which itself helps to precipitate the inefficient regeneration and muscle fibre loss that characterises the later stages. There are no current treatments that prevent muscle fibre loss. We hypothesise that if matrix remodelling can be prevented by MMP inhibition during the early stages of muscular dystrophy, fibre loss will be reduced and regeneration made more efficient. This hypothesis is based upon two main findings, firstly matrix metalloproteinases (MMPs), specifically MMP9, are up-regulated in the muscle of mdx mice where they localise to areas of inflammatory infiltrate and muscle fibre degeneration and secondly that MMP inhibition has been previously shown to ameliorate muscular dystrophy in the mdx. To test this hypothesis we will use two animal models both of which are associated with progressive forms of muscular dystrophy namely; the dystrophin deficient mdx, which is a model for Duchenne Muscular Dystrophy and the FKRPMD mouse which is a model for LGMD2I. Both have disruption of the linkage between the muscle fibre and the basement membrane, the mdx does this via an alteration in a cytoskeletal protein (dystrophin) and the FKRPMD via a disruption in the binding between alpha-dystroglycan and LG domain containing proteins laminin and perlecan in the extracellular matrix. We will initially treat mice of two different stages of the disease for 3 months at three dose rates by oral gavage of AZD1236, a potent, selective, orally bio-available, MMP9/12 inhibitor that has been studied in Phase 2a clinical trials in COPD patients via oral administration. We will then select the best age and dose rate for an extended 6 month study involving exercise induced exacerbation of the pathology. The aim is to determine if AZD1236 is sufficiently effective to warrant a clinical trial.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Phase II study of the impact of AZD4017, a selective 11beta-HSD1 inhibitor, on biochemical markers of bone turnover in post-menopausal osteopaenia
Funder: Medical Research Council

Abstract: Age-related osteoporosis is a major health problem affecting ~30% of post-menopausal women. It is caused by an imbalance between bone formation and bone resorption leading to net bone loss. Current medications do not directly address the underlying cause of the imbalance and there is a need for additional medications to reduce fracture risk, particularly those that correct the age-related abnormality in bone turnover. Age-related bone loss shares similarities with that due to glucocorticoid excess. We have shown that osteoblasts generate glucocorticoids through expression of the 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) enzyme. The expression/activity of 11b-HSD1 in osteoblasts increases dramatically with age and 11b-HSD1 activity reduces bone formation markers and increase bone resorption. We thus hypothesise that 11b-HSD1 is a mediator of age-related bone remodelling imbalance. Furthermore we propose that therapeutic inhibition of 11b-HSD1 activity will have a dramatic effect on bone, effectively reversing changes seen with age. Our hypothesis will be examined in a clinical trial of a selective 11b-HSD1 inhibitor, AZD4017, or placebo in women with reduced bone mass. Women with osteopaenia will be recruited at two specialist bone units. Subjects will be >55 and post-menopausal and consenting subjects will be randomised to either 400mg BD of AZD4017 or placebo for 3 months. Serum will be taken for biochemical markers of bone turnover; novel markers of glucocorticoids action on bone; HPA axis function, and measures of drug safety. Urine will be taken for measures of 11bHSD1 activity. Bone density will be measured by DXA and pQCT. Subjects will be seen regularly during treatment and 90 days after. This trial will clarify the contribution that 11bHSD1 activity makes to age-related abnormalities in bone remodelling. Furthermore it will clarify whether AZD4017 has the potential to reverse age-related bone disease as a treatment for post-menopausal osteoporosis.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL
Title: Improved cartilage regeneration through the selection and use of highly chondrogenic subpopulations of bone marrow mesenchymal stem cells
Funder: Medical Research Council

Abstract: We have identified the inducible tyrosine kinase-like orphan receptor 2 (iROR2) as a cell surface marker of the most chondrogenic mesenchymal stem cells (MSCs). Its increased level of expression on undifferentiated MSC clones is associated with a higher volume and quality of engineered cartilage after chondrogenic differentiation and tissue engineering on three-dimensional scaffolds. We now want to exploit this discovery for future clinical use. There will be three strands of work exploring a) the feasibility of producing a therapeutic based on iROR2+ve selection of MSCs b) the immunological properties of iROR2+ve and iROR2-ve cells and c) the mechanism of iROR2 enhancement of chondrogenesis. Feasibility of producing a therapeutic will be investigated by developing a FACS or magnetic cell sorting (MACS) method that is reliable and leads to the production of predictably more chondrogenic cells. Once a production method has been established using human cells we will then investigate if immunosuppression is needed for the xenogeneic implantation of human MSCs into sheep or if the immune privilege of the implant site and the immunoregulatory properties of MSCs will make immunosuppression unnecessary. A pivotal sheep study will then test the efficacy of human iROR2+ve cells in a sheep articular cartilage repair model compared with controls. We will use a new sheep model in which mature tissue engineered cartilage is integrated with the host natural cartilage using our "Cell Bandage" technology. Immunological properties of iROR2+ve and -ve MSCs will be investigated using standard in vitro T cell proliferation assays. The role of ROR2 in MSC chondrogenic differentiation will be investigated by knock-down of the ROR2 gene and by its upregulation in vitro. Zinc-finger technology will be used to ensure stable expression of the full-length gene or the antisense sequences, with evaluation of chondrogenesis in our cartilage tissue engineering ass


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