NIHRDataInsights/HRCSData huggingface dataset:
Title: INOVCF-Innovative non-CFTR Approaches for Cystic Fibrosis Therapy
Funder: Cystic Fibrosis Trust

Abstract: 1) generating models of cells suitable for physiological therapy / drug therapy models; 2) gaining mechanistic insights into acid/base homeostasis and regulation of anion transport; 3) innovative non-CFTR therapy approaches


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: Dietary manipulation to improve glycaemic control in young people with cystic fibrosis and altered glucose handling: a feasibility study
Funder: Cystic Fibrosis Trust

Abstract: Feasibility study investigating dietary manipulation to improve glycaemic control in young people with cystic fibrosis (CF) and altered glucose handling.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CONGENITAL DISORDERS
Title: Project Breathe
Funder: Cystic Fibrosis Trust

Abstract: Development of a robust platform to test and further develop SmartCareCF - a unique collaboration between Cystic Fibrosis Trust, Microsoft, University of Cambridge and Magic Bullet Medical to improve the outcomes and quality of life for patients with chronic conditions through remote monitoring, virtual clinics, machine learning and analytics.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CONGENITAL DISORDERS
Title: Quantifying bronchiectasis severity in cystic fibrosis
Funder: Cystic Fibrosis Trust

Abstract: Advance machine learning technology in patients with CF to better characterise abnormal airways that may be filled with mucus. An automated computer tool that calculates the number of abnormally dilated airways and the volume of lung comprising abnormally dilated airways, will create a more sensitive measure of disease worsening in CF that can be used in future drug trials. In turn, a more sensitive drug trial measure of abnormal airway dilatation may allow fewer patients to have to be included in a trial, making trials cheaper and easier to run.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CONGENITAL DISORDERS
Title: Development of in vitro Transcribed mRNA Therapeutics for Cystic Fibrosis
Funder: Cystic Fibrosis Trust

Abstract: Develop a new therapy called CF-mRNA that will replace the missing channel in the lung and so correct the mucus problem. 1) optimise CF mRNA by comparing variations of the molecule in a simple test-tube reaction which can have a big effect on its stability and efficiency and can only be determined by experimentation. 2) wrap the CF-mRNAs in a protein/ fat mixture called a nanoparticle that protects the mRNA and can carry it through mucus and into the affected lung cells. The CF mRNAs will be compared for their potential to correct CF in human CF cells in the laboratory as well as in CF mice. 3) develop this therapy for use in all CF patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CONGENITAL DISORDERS
Title: Bioinformatics of human behaviour: from epigenetic silencing of Frataxin to ethomics in Friedreich’s Ataxia
Funder: Medical Research Council

Abstract: This research project focuses on linking gene expression changes in human subjects with objectively measurable natural behaviour (ehtomics) in humans. We focus on Friedreich’s ataxia (FRDA), a currently incurable and devastating disease caused by the expansion of a repetitive DNA GAA repeat within the non-coding region of the Frataxin gene that leads to the gene becoming compacted by heterochromatinisation, inaccessible and repressed (1, 2). We and others have recently shown that this compacted state can be overcome by deacetylase inhibitors which are therefore a potential disease- modifying therapy (3, 4). It is FXN deficiency that is thought to render the cells sensitive to oxidative damage and impairs mitochondrial function. We will model how changes in frataxin gene expression and chromatin structure translate into gene expression changes (RNAseq) at the genome-wide level in disease-relevant cell types and thereby identify the molecular pathways which lead to the disease phenotype and correlate these with identifiable measurements of changes in behaviour. FXN deficiency in FRDA leads to poorer proprioception, motor control and fine motor coordination that are identifiable and measureable so far only through coarse grained clinical standard measures. The overall plan is to gain insight into FRDA pathogenesis by tracking disease progression and correlating gene expression changes with disease severity longitudinally. This project has been seeded by the development of a novel behavioural biomarker using FRDA patients and controls (Faisal, Festenstein MS in prep 2017; 5,6) and will allow us to identify causal molecular pathways that are directly relevant to the patient


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: Common congenital malformations in humans
Funder: Medical Research Council

Abstract: Malformations are the commonest cause of death in UK children under five years of age. The aetiology unknown in most cases. We aim to understand individual loci, mechanisms and interaction that the genetic basis of several different major malformations using samples from large cohorts of patients with; cleft lip and/or cleft palate, bilateral renal agenesis and eye malformations. To identify new disease genes we utilise three main human genetics approaches: Apparently balanced chromosomal rearrangements (ABCR) This approach has been the mainstay of our gene identification work but has recently proven useful in developing techniques to look at long-range control of developmentally regulated genes. Recurrent breakpoints on 17q24 led us to characterise regulatory mutations more that 1.3 Mb centromeric and telomeric to SOX9 as a major cause of Pierre Robin sequence, an important subset of cleft palate. We have also identified ESRRG as a candidate gene for human renal agenesis. Array-based comparative genomic hybridisation (aCGH) to identify microdeletions associated with specific malformations. Overlapping deletions identified at 5q22 in five patients have identified a locus for Pierre Robin sequence on 5q close to the FBN2 gene. Linkage analysis in families. We have identified the locus for a rare but interesting human condition called ophthalmoacromelic syndrome (anophthalmia with oligodactyly) on 14q. Many of the chromosomal abnormalities that we work on appear to be acting through disruption of cis-regulation of developmentally, dosage critical gene. We are continuing our work into the long-range control and developmental function of SATB2 as a cause of cleft palate. We have also been collaborating with Professor van Heyningen on identifying cis-regulatory mutations in PAX6 as a case of aniridia. As part of our P50 NIDCR-funded project we have also started taking a systematic approach to investigate the utility of developmental gene expression analysis in mouse embryos as a method of identifying disease genes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CONGENITAL DISORDERS
Title: Predictive measures to stratify clinical outcomes in children and adults with Gaucher disease and responses to specific therapies
Funder: Medical Research Council

Abstract: To build a research consortium that will promote discovery and improve outcomes for patients with Gaucher disease, our overarching aim is to refine treatment using clinical stratification and severity categories based on therapeutic responses. Life-quality is impaired, survival is reduced and crippling skeletal disease, marrow failure, visceromegaly, cancers with disabling neurological effects, including late-onset Parkinsonism, supervene. Disease discrepant between siblings and identical twins, shows that clinical and treatment responses are not determined by genotype alone: in-depth phenotyping is critical for stratification and therapeutic advance. National specialized centres for Gaucher disease will recruit at least 85% of UK patients (~250) with a focus on neurological and osseous disease as research strands in major areas of disability in adults and children. Stratification will facilitate generation of a dynamic platform for advancing therapy and further understanding of disease causation. High-resolution stratification into clinical cohorts will use validated disease severity and life-quality scores to annotate therapeutic responses; we will explore the predictive value of the activated inflammasome and bioactive lipids, as well as established plasma enzymatic and chemokine biomarkers. Partner biostatisticians (MRC external staff) will conduct time-to-event and regression modelling analyses to develop treatment cohorts based on dosing studies (enzyme therapies) and stage of intervention; serial biological samples will be stored and data entered on the custom-designed central national Gaucher register accessed at all centres. Genzyme-Sanofi, Shire HGT and Actelion Pharmaceuticals will share expertise, registry data and key resources; success in building the consortium will render stratified patient cohorts in national Gaucher centres highly attractive for innovative clinical trials and commercial development of predictive and diagnostic biomarker toolkits.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CONGENITAL DISORDERS
Title: Evaluating genetic therapeutics in ciliopathies
Funder: Medical Research Council

Abstract: Aims: Investigate novel therapeutic approaches in Bardet-Biedl Syndrome (BBS) using genetic therapeutic agents which have demonstrated proof of principle in other recessive conditions: antioligonucleotide (AON) therapy and read-through therapy. Objectives: 1. Show that targeted AON therapy could be developed to have a measurable therapeutic effect on BBS patients with frameshift/splice site mutations (n=27, 9% of the BBS patient population). 2. Investigate the efficacy and clinical application of read through therapy on BBS patients with paired nonsense mutations (n=43, 14% of the BBS patient population). Methodology: An AON with high exon skipping potential would be designed. To determine whether the AON has exon-skipping potential in vitro I would culture immortalised fibroblasts from unrelated BBS patients as well as controls in the absence and presence of the AON. Once the specificity has been established the most effective treatment dose must be determined. Subsequent investigations will determine the phenotypic effect, efficacy and side effect profile as well as the suitability of this drug for a clinical trial. Read-through therapy has already proven to deliver very robust results in renal cells transfected with a number of common mutations from a variety of ciliopathies. The aim is to reproduce these findings in other cell types such as the eye. Providing this delivers the expected results, I would investigate the effect of this drug on measurable outcomes including visual deterioration and body mass index. An application will be made for ethical approval to introduce Ataluren into a clinical trial. Opportunities: We have access to a large patient population (>400) through the nationally commissioned BBS clinic, and close ties with a very proactive patient support. If these therapeutic strategies deliver the expected results we will implement them into clinical practice and develop them further for use in other ciliopathies.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CONGENITAL DISORDERS
Title: Investigation into the role of ceramide in the pathogenesis of cystic fibrosis lung disease
Funder: Medical Research Council

Abstract: Cystic fibrosis (CF) is the most common genetically acquired life-limiting disorder in the UK. Lung disease is responsible for over 95% of morbidity and mortality, the exact pathogenesis of which remains poorly understood. There is an acute need for the development of novel therapeutic approaches. Raised levels of the sphingolipid ceramide have been described in a CF mouse model that are associated with lung inflammation, a key feature of human CF lung disease. In this Clinician Scientist Fellowship proposal I will combine primary bronchial epithelial cells and human CF lung tissue with the latest mass spectrometry techniques to accurately measure and image ceramide in the airway epithelium. I will then examine a potential mechanism whereby ceramide may accumulate in the plasma membrane due to reduced acid ceramidase activity and cause inflammation. I hypothesise that ceramide accumulates in microdomains of the plasma membrane in CF airway epithelial cells that causes NADPH oxidase to cluster resulting in raised production of reactive oxygen species, increased production of inflammatory mediators and airway inflammation. I will also examine whether the altered ceramide metabolism is associated specifically with defective CF transmembrane regulator function (CFTR). Finally I will investigate the potential therapeutic use of recombinant acid ceramidase in models of CF lung disease to reverse the accumulation of ceramide and reduce airway inflammation. This fellowship will advance knowledge, improve methodology and answer key questions that may support ceramide metabolism as a potential novel therapeutic avenue for CF lung disease including the use of recombinant acid ceramidase.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: In vitro and in vivo preclinical testing of pericyte-engineered grafts for correction of congenital heart defects
Funder: Medical Research Council

Abstract: Unmet clinic needs: Congenital heart disease (CHD) is the most common type of and the first cause of mortality due to a congenital defect. In 2004, the U.S. hospital costs for CHD totalled $1.4 billion, with surgical costs for repeated operations being estimated to be over $2.4 million for every 100 cases. The main problem is that prostheses employed in congenital cardiac surgery are not perfect, e.g. they need to be substituted a few years after implantation. How this new technology will fill the gap: Incorporation of stem cells (SCs) shall confer prosthetic grafts with the characteristics of a living tissue that grows and remodels in a physiologic manner in parallel with cardiac and whole body growth. We gathered promising data, prior and after our initial outline application to the MRC, regarding the unique properties of pericytes from neonatal heart and umbilical cord. Here, we propose to use pericytes to engineer valved vascular conduits to be used for the reconstruction of right ventricular/pulmonary artery defects. Experimental plan: The project consists of three objectives. Objective 1 (workpackages [WP] 1&2): generate stocks of quality assured swine pericytes and determine the reproducibility of graft manufacture. Objective 2 (WP3): provide proof of principle of feasibility of the pericyte-based approach in a newly developed piglet model. Objective 3 (WP4): preparatory engagement with regulatory bodies. WP include milestones (M) and contingency measures (CM) for risk containment.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CONGENITAL DISORDERS
Title: Development of a novel repurposed drug treatment for the neurodegeneration and diabetes in Wolfram syndrome
Funder: Medical Research Council

Abstract: Wolfram syndrome is a rare form of diabetes and neurodegeneration, and a target for the International Rare Diseases Research Consortium (IRDiRC) goal of developing new treatments for rare diseases. The prognosis is poor as most patients die prematurely with severe neurological disabilities such as bulbar dysfunction and organic brain syndrome. There is no cure, and no treatment that will arrest or delay the progress of the disease. We are developing a novel, repurposed drug therapy suitable for the management of patients worldwide with Wolfram syndrome by promoting cell survival via increased p21cip1 expression and reduced apoptosis, leading to an overall improvement in patient relevant outcome measures. To date we have: (1) identified the cell cycle regulator p21cip1 as a therapeutic target; (2) undertaken a drug screen and identified sodium valproate (SV) as a regulator of p21cip1 expression, and reduced endoplasmic reticulum stress and apoptosis markers; (3) have applied for and gained EMA and FDA Orphan Drug Designation for SV for the treatment of Wolfram syndrome; (4) received EMA protocol assistance and engaged closely with patient groups to design a pivotal clinical trial with patient relevant endpoints. We now seek further funding to allow progression of the project according to a defined translational and commercialization strategy encompassed within a business plan that includes: (1) undertaking an efficacy study of SV to delay or prevent progression of neurodegeneration and glucose intolerance in a mouse model of Wolfram syndrome; (2) undertaking a clinical trial to assess safety and tolerability of SV in patients with Wolfram syndrome; (3) reaching technical readiness for a future pivotal clinical trial to form the basis of an EU application for marketing authorization. This will move the technology along the translational pathway towards adoption as the recommended treatment in the clinic.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: CONGENITAL DISORDERS
Title: Pre-clinical studies on a novel prodrug delivery technology for cystinosis.
Funder: Medical Research Council

Abstract: This project seeks to evaluate the safety of cysteamine prodrug CF10 in an appropriate model and obtain sufficient pre-clinical data to support an MHRA application for clinical trials approval. We have designed CF10 to address the unmet clinical need for a better treatment for cystinosis, a rare autosomal recessive disease characterized by raised intracellular levels of cystine. Untreated, cystine crystals accumulate in the lysosomes of all cells, leading to permanent organ damage and usually death by ten years of age. It is treated with oral cysteamine (as the bitartrate salt Cystagon or the sustained release bitartrate form Procysbi), which reduces lysosomal cystine levels and delays disease progression. However, both of these medicines cause problems that adversely affect compliance. CF10 was designed to address the problems of cysteamine administration, aiming for: minimal taste and smell; low gastric irritation; good oral bioavailability; evasion of 1st pass metabolism, requiring fewer and lower doses; and, release of cysteamine systemically on the surface of cells for its rapid uptake. The preliminary evidence supports progression of the prodrug CF10 into pre-clinical studies. In this project, GMP certified CF10 will be tested for genotoxicity and its toxicity evaluated in a suitable model, providing safety and toxicokinetic data to guide dosing for a 1st in man clinical trial. Concurrently, a liquid formulation of CF10 suitable for paediatric clinical trials will be developed. The results will support applications for funding and regulatory approval to progress CF10 to a 1st in man clinical trial, alongside more detailed pre-clinical studies in preparation for the second phase of clinical trials. Clinical cystinosis experts are involved in the design of clinical trials and industrial support brings commercial expertise to the development of CF10.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CONGENITAL DISORDERS
Title: MICA: To evaluate the role of the histamine four receptor (H4R) in the clearance of lung pathogens using the H4R antagonist UCB1344778
Funder: Medical Research Council

Abstract: We have evidence suggesting that bacteria-derived histamine in lung fluids impairs neutrophils (PMNs) antimicrobial functions by engaging histamine receptors, in particular the H4R. We will therefore address the role of the H4R in pathogen clearance by using the H4R antagonist UCB1344778. The following two objectives with be achieved: A. To test the role of H4R activation in modulating PMN phagocytosis in vitro. We will investigate whether treatment of human or murine PMNs with histamine prevents capture and killing of respiratory pathogens found in CF lungs (P. aeruginosa, and Burkholderia cenocepacia). To prove that histamine-mediated inhibition of PMN phagocytosis is caused by engagement of the H4R, we will investigate whether UCB1344778 can reverse the inhibitory effect of histamine on PMN phagocytosis. We will validate UCB1344778 as a potent booster of PMN phagocytosis and pathogen clearance. B. To test the role of H4R activation in modulating mouse PMN phagocytosis in vivo. We will investigate whether bacteria-derived histamine is responsible for the impaired phagocytic activity of pulmonary PMNs in a mouse model of CF. To this end we will infect BALB/c mice with the stable mucoid P. aeruginosa CF sputum isolate (NH5833A) to induce a mouse model of CF which mimics human CF pathology. Two approaches will be used to prove the inhibitory role played by the H4R in the clearance of lung pathogens in this CF mouse model. First, we will create a histidine decarboxylase (hdc)-null derivative of P. aeruginosa NH5833A, which will be unable to produce histamine. We will compare lung pathology and lung bacterial clearance in mice infected with the parental isolate vs. those infected with the hdc-null mutant. Second, we will compare lung pathology and lung bacterial clearance in mice infected with both isolates, but treated orally for 7 days with UCB1344778.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: Gene therapy for CLN5 Batten disease
Funder: Medical Research Council

Abstract: CLN5 Batten disease is a lethal paediatric inherited neurodegenerative lysosomal storage disorder caused by mutations in the CLN5 gene. Children with CLN5 Batten disease suffer progressive and devastating dementia, motor decline, epilepsy, visual failure and ultimately premature death. There is no treatment for CLN5 disease and there is a desperate need for a novel effective therapy. We propose a preclinical assessment of AAV-mediated gene therapy to restore expression of CLN5 in both the brain and eye to prevent lethal neurodegeneration and maintain quality of life through prevention of blindness, respectively. This will be assessed using a CLN5 deficient mouse model that presents both the brain and eye symptoms observed in patients. We will also examine safety associated to over-expression of the CLN5 gene and biodistribution. Two vector iterations will be tested side-by-side administered either via intravenous or intracerebroventricular injection to verify which has the greatest therapeutic efficacy in the brain and by subretinal administration to the eye in pre-symptomatic neonatal mice as proof-of-concept. When optimisation of the individual treatments has progressed, combination therapy of both brain and eye will be performed in older early symptomatic mice to mimic the clinical scenario of treatment following diagnosis. A number of key factors support this proposal: (A) CLN5 protein is a soluble enzyme that can be secreted from a cell and taken up by another, amplifying the therapeutic effects of gene delivery, (B) The applicants and collaborators have significant experience in rescuing mouse models of neurodegenerative diseases using gene therapy, and (C) encouragingly, there is evidence supporting the therapeutic efficacy of AAV9-mediated gene therapy in the brain of a sheep model of CLN5 disease. This project is an essential first step towards treatment for CLN5 disease.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CONGENITAL DISORDERS