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Rare Diseases Research Newsletter of the Rare Diseases Translational Research Collaboration Issue 14 August 2016 Of Collaborations and Consortia Inside this issue 2 3 7 8 10 11 13 14 15 16 17 18 19 22 Global Metabolomic Profiling HPO Workshop Report Research Symposium 2016 Prof. Fiona Karet Renal Theme Lead Rare Renal Disease Day Patient Day “Think Research” Eye Theme Update Fellows’ Day 2016 Introducing a RD-TRC Fellow Data Pipeline Data Co-ordinators CRDN Summit 2016 Save the Date Contact Us In June, the RD-TRC completed a very successful week hosting Human Phenotype Ontology (HPO) workshops across many of our disease themes. We have received strongly positive feedback from the participants, including Professor Peter Robinson from Berlin, and his colleague Melissa Haendel from Oregon, who travelled to the UK to help us in this endeavour. I believe many of you have established links with Peter and Melissa to take HPO development forward in future months. This is going to be enormously helpful when we come to upload data relating to our deeply phenotyped cohorts onto the core database. The lead-up to the summer has been an exceptionally busy period, not least because we have all been re-applying for support from NIHR for Biomedical Research Centre status. We were very pleased to see a section on the BRC form specifically asking about engagement with the RD-TRC in the future. This is clearly an endorsement of the work that we have been doing over the last four years, and places the collaboration in a great position for future work on rare diseases. Thank you for all who attended the workshops analysing metabolomic data generated through the RD-TRC. We will be in touch in the near future about a joint publication from our consortium which will hopefully describe the impact of metabolomic analysis across the range of diseases that we study. Clearly the phenotypic data that we are collecting will be of major importance here. The data team will be in touch in the near future for a data collection ‘push’ to enable a high-impact output from the collaboration. We look forward to seeing you at the Annual Conference in September. I am pleased to say that Professor Paul Lasko will be coming over from Canada to provide the keynote lecture. Have a good break in the intervening period. Prof. Patrick Chinnery RD-TRC Co-Chair Global Metabolomic Profiling Providing new insights into the pathobiology of rare diseases Until recently, existing techniques to assess metabolism were limited to a very narrow approach, usually targeted to assess a single substance or biochemical pathway. However, recent technological advances in the field of metabolomics now permits assessment of thousands of metabolites simultaneously. This provides a snapshot of the multiple interconnected dynamic processes occurring in a tissue, organ or system. It can be used to comprehensively assess the changes in metabolite milieu that occur in disease, and also in response to a treatment. In many areas of medicine, this technology has allowed previously unrecognised metabolic derangements to be detected. Therefore, metabolomics may provide insights which advance mechanistic understanding of diseases, facilitate biomarker discovery and improve disease phenotyping. Access to this technology has recently been provided by the NIHR Rare Diseases TRC, using the Metabolon DiscoveryHD4™ platform. This platform uses 2 ultra-high performance liquid chromatography methods coupled with tandem mass spectrometry and a reference library of >14,000 small molecules, allowing analysis of a large repertoire of metabolites. Access to Metabolon has allowed our group to assess the ‘metabolome’ in pulmonary vascular diseases, including pulmonary arterial hypertension. Historically, this was considered a disease process localised to the lung vasculature. However, it is now recognised that more widespread metabolic disturbances exist, includes alterations in energy metabolism and evidence that metabolic factors are implicated the way that the right heart adapts to stress. The metabolomics data in our patient cohort will be integrated with genomic and clinical data as part of a deep phenotyping strategy. Additionally, further analysis of metabolites and biochemical pathways of interest may direct the search for new disease specific biomarkers. Similarly, these applications will be relevant to many other diseases and will continue to provide new insights into disease pathobiology in the future. Dr. Kasia Zalewska, Research Fellow Pulmonary Vascular Diseases Unit, Papworth Hospital, Cambridge Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 2 HPO Workshop – Rachel Spring Reports on The Human Phenotype Ontology About HPO An ontology is a computational representation of a domain of knowledge based upon a controlled, standardised vocabulary for describing entities Peter Robinson and the semantic relationships between them. It enables the linkage and integration of datasets. Each term in the HPO describes a phenotypic abnormality. Terms are ordered into a hierarchy of relationships. Peter started work on HPO after starting using the London Dysmorphology Database, "I had 20 search terms but still over 200 candidates, I then added one or two more terms and the results went to zero. The search just could not cope with ‘fuzzy’ and inexact matches" you needed a structure for similar terms and grouping terms into families, which could be matched. This characteristic became ore important when you compare species. The HPO terms are species neutral - this is important. Only 20% of the 20,000 genes are explained by phenotypes in humans; add in mouse models and other species and over 80% of the genes have a phenotype target. As you try and understand each individual’s genome you find around 100,000 variants of which perhaps 40,000 match gene targets, 95% of these can be explained by common variants leaving around 500 changes that could be of interest. This combined knowledge is especially important for rare diseases as it can trim this long list of 500 to a smaller list capable of identification in small patient groups. Developing the HPO Most of the terms in the HPO have come from medical literature, Orphanet, DECIPHER, and OMIM. HPO currently contains approximately 11,000 terms (and is still growing) and over 115,000 annotations to hereditary diseases. The HPO also provides a large set of HPO annotations to approximately 4,000 common diseases. To be a valid clinical tool, Peter, Melissa and their teams, are collaborating with experts and specialist medical communities across many countries to make the ontology as robust as possible. The RD-TRC workshops were intended to improve the understanding of rare disease specialists in the UK and encourage investigators to become part of the community effort. As the breadth and depth of annotation grows, tools will be developed to improve diagnostic rates, share the expertise of specialists with non-specialists, and improve the understanding of rare diseases to benefit those suffering from them. Things to come As the ontology matures, there are several challenges the team hopes to address in the future. For example, the development of HPO for common diseases where there is a lifestyle or environmental aspect, for example alcohol use or toxin exposure. This is an active research programme using GP data where case notes will automatically be converted into HPO terms for population studies. (Cont. p. 4) Peter trained as a physician and studied maths and computer science. As a paediatrician at Charité in Berlin, he developed an interest in molecular genetics and bioinformatics. He began developing the HPO in 2007 and it has been a decade-long labour of love. He is due to move to the Jackson Laboratory for Genomic Medicine in Connecticut in August. Melissa Haendel Melissa is an Associate Professor at the Oregon Health & Sciences University. Her background is in developmental molecular neurobiology but driven by the ambition to make better use of the plethora of under-utilised data, she has developed an interest in ontologies and semantic data integration projects. Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 3 Contributing to the project Peter and Melissa see the work being done to improve the terms and their relationships in the ontology as crucial to the ultimate power of the tools they are creating such as the phenomiser, exomiser, genomiser and others. While it is ‘under the bonnet’ work that ultimately will be unseen, it will not go unappreciated or even unattributed. They are very happy to name contributors in publications and on the websites. What to contribute All feedback is valuable! No one would be more delighted than Peter and Melissa if you decided to lock yourself and colleagues in a room for a week to map the ontology for your whole Theme. RD-TRC HPO Workshop Report (Continued) There is also a big project looking into cancer funded by the National Cancer Institute in the US. In cancer there is a good thesaurus of terms from which the clinician can recognise the cancers, but it is a long way from a biological ontology, it has features of the disease but the disease may have multiple expressions across different body systems. The team is also looking to integrate the tools available and to spending some time with ‘user friendly designers’ to improve the experience and make it more intuitive for the non-geeks. Tour of the Tools Monarch’s Phenotype Profile Analysis page allows you to search by phenotype(s). But even if it were just a case of commenting on the terms relating to one disease this would be very valuable and welcome work. How to contribute Once you’ve viewed the ontology and reviewed the relevant terms and relationships, these are the options for letting the team know your comments or suggestions for revision: • Melissa’s created a shared spreadsheer for comments arising from this workshop - select the right tab for your Theme: https://docs.google.com/spreadsheets/d/1yzjR1sxWYuCzXCnHK2EwXc41GUsmBOm6wQI-PWIkT0/edit#gid=1641274682 • Peter’s HPO Tracker (register for a login first) is a public mechanism for comment: https://github.com/obophenotype/human-phenotype-ontology/issues The Exomiser is a Java program that finds potential diseasecausing variants from whole-exome or whole-genome sequencing data. Starting from a VCF file and a set of phenotypes encoded using HPO it will annotate, filter and prioritise likely causative variants. http://www.sanger.ac.uk/science/tools/exomiser PhenIX is an exome analysis tool that utilizes phenotypic similarity of diseases associated with the genes harboring candidate variants to the phenotypic profile of the individual being investigated. http://compbio.charite.de/PhenIX/ Viewing the ontologies for purists There are various ways to navigate the ontology. Here are two: Via HPO: The HPO can be viewed and searched via the HPO website’s tools section or directly via this link: http://compbio.charite.de/hpoweb/showterm?id=HP:0000118 Via Ontobee: The Ontobee website contains many ontologies, the link to the HPO is here: http://www.ontobee.org/ontology/HP The Monarch Initiative aims to provide easy-to-use tools to navigate this data landscape, services for other resources, and educational outreach regarding the production of structured data for biomedical discovery. https://monarchinitiative.org/ The Patient Archive is a platform for patient data management and collaborative diagnosis. It allows for text mining of clinical summaries for HPO terms. And for consented patients, data can be shared and exchanged to enable diagnosis and clinical discovery. http://patientarchive.org/#/home Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 4 RD-TRC HPO Workshop Report So what did we learn? At the heart of the work of the RD-TRC lies the development of a national federated database for in-depth phenotyping. Underpinning this work is the adoption of HPO as the informatics scaffolding for data collection. In medical informatics there are multiple classifications and ontologies that have been developed and the workshop helped address why HPO was chosen. The workshops with Melissa and Peter were a very real ‘road test’ of the importance of HPO to our work. As different projects led different discussions on the use of HPO it became clear that the underlying HPO framework could contribute to across the board. Each presentation starting with an HPO outline of the latest developments: Tools that supported the capture of ‘full’ patient profiles, links and look-up to different disease databases and the integration of genomic and other data, often across species. For the Rare Diseases Peter did the maths … Dr. Roger James RD-TRC IT Director “There are a few hundred thousand variants across the human population, of these perhaps 40000 are in the target region and from these around 95% can be eliminated as common variants, you are still left with a long list of perhaps 500 candidates which could be of interest. For the Rare Diseases where patient numbers are small this is a statistical challenge. Perhaps 20% of the 20K genes are associated with a phenotype in humans, but this goes to 80% if you include all animal species”. In introducing HPO Melissa and Peter explained how the HPO worked as a framework for the identification and comparison of disease aetiologies. The idea of HPO is that it functions as a biology based computation scaffold which enables other ontologies to be integrated and searches to be extended [see the comments earlier in the report on the problems of search]. The introduction also gave a glimpse of the future - funded developments in re-coding the existing cancer ontologies into the biologically structured concepts of HPO and a major study in auto-coding HPO terms for the common diseases from existing medical records. The workshop was an interesting ‘road test’ of HPO and its use in the RDTRC. In some disease areas the use of HPO was well established and mature, the Eye Diseases are the example here where scientifically and metaphorically the organ is easy to observe and dysmorphologies well structured and characterised. This is in contrast with the Central Nervous System Disorders where the characterisation of disease is less obvious and where cross species models are difficult to develop. For some diseases, including Cancer and Respiratory, the source of the disease is a combination of the organ susceptibility and some environmental challenge. Understanding the patterns of the disease also requires knowledge of the environment. Early days here but the big developments in cancer encoding and integration of primary care records will require the development of the ‘environmentalome’ - or the characterisation and encoding of the challenge factors which will be the path to a breakthrough. For Skin and Musculoskeletal existing speciality disease classifications are in widespread use. The work here is to extend HPO to make use of these standards. Of importance here is the ‘openness’ of the HPO to incorporate other ontologies, for example the cross species skeletal ontology Uberon, this re-uses existing work but also integrates multiple studies. Both theme explored how their existing ontologies could be ‘welded’ into HPO. The ontology allows us to combine data from different species and different descriptors Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 5 RD-TRC HPO Workshop Report So what did we learn? (Cont.) Other themes, such as Cardiovascular and Paediatrics, were interested in how HPO could help deliver the bio-informatics frameworks for further analysis. Here help was requested for the conversion of ICD codes into HPO (various tools are available!) and there was also interest in the ‘Phenogrid widget’ to identify possible causative genes based on Phenotype patterns. In what is best described as a ‘Mexican wave’ of views the potential is significant and it hoped we could contribute to the feedback to develop the idea further particularly in the development of some filtering options. For Immunology the discussion was around where HPO fits alongside the collection of clinical data, for example Immunology makes use of a large battery of lab tests that do not fit neatly into a biological ontology. Aside from helping refine and extend the HPO ontology the consensus was whilst HPO is central to the structuring and integration of disease descriptors it is not always the best approach for clinical data collection. Conversion and mapping [the service provided by the RD-TRC data coordinators] is an integral part of the research work. While human readers best understand data that is provided as free text, computers can better analyze data that is represented with ontologies. In order for computers to learn how free text corresponds to ontologies, a text corpus (such as the HPO corpus) is required, based on which a computer can learn this relationship. Credit: Tudor Groza To make use of all the data you need something more than just search For Haematology and Renal the conversations were around how the HPO could be refined with the findings from the latest research work. Current work, which uses the HPO to increase the statistical power for gene discovery, was referenced. Our discussion was around the easy to use service, offered by Peter & Melissa, to add new terms to HPO via the GitHub tracker. As an informatician [HPO geek!] I was excited by the technical services (such as BioLark for term extraction from medical records), the integration of different ontologies and the 5 star tools to measure the quality of phenotyping (and the observed improvement to phenotyping depth & coverage). The future developments are also ones to watch – the developments of patient entered phenotype data (lay persons synonyms), the ‘matchmaker’ & ‘phenopackets’ initiatives for the sharing of phenotypic data and the integration with care systems (such as Open.EPIC). Our thanks to Melissa and Peter for what was a tremendous and informative week for all attendees. We intend to work closely with them in the future and also to keep everyone aware of their latest developments. We start this with the HPO resources & links document, which will be made available on the web [available at http://rd.trc.nihr.ac.uk/news-and-events/hpo-workshops-june2016/] Dr. Roger James RD-TRC IT Director Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 6 RD-TRC Annual Research Symposium 15th September 2016, Cambridge If you have been invited but still need to register please follow this link: http://www.profbriefings.co.uk/rdtrcsymposium2016/index.html Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 7 Focus on Professor Fiona Karet RD-TRC Renal Theme Lead Nicola West Reports Professor Fiona Karet, our Renal Theme Lead, is one of the world’s leading researchers in rare kidney disease. But it very nearly didn’t happen; early on in her career, Prof. Karet had believed she would become a medical educator. And then three things happened. Firstly, the medical graduate from University College London, who had come to Cambridge in 1990 as a registrar, was awarded a fellowship from the National Kidney Research Fund (now Kidney Research UK) and began a PhD, where she characterised what was then a little-known protein in the kidney, endothelin. Prof. Fiona Karet Renal Theme Lead Secondly, Prof. Karet came across a family in her weekly clinic who had difficult hypertension (high blood pressure) which was clearly inherited; not only was it passed from generation to generation but it was also associated with the early death of an uncle at just 29 years from a stroke – one of the primary signs of a particular type of inherited hypertension. And thirdly, Prof. Karet attended an American Society of Nephrology (ASN) conference in Boston, where she heard Professor Richard Lifton from Yale University School of Medicine present on a new rare genetic cause he had discovered for familial hypertension, and the specific treatment that would normalise blood pressure. Prof. Karet said: “I asked if he [Prof. Lifton] could analyse a blood sample from the family to see if they had the same mutation he had spoken about, which would explain their high blood pressure. The advantage of knowing a genetic cause of something that is handed down from generation to generation is that you can test family members at risk of the same condition; they can then modify their treatment and/or their lifestyles to minimise harm. Prof. Lifton confirmed that the family did indeed have the mutation and we changed their treatment immediately to something unusual but known to work well. By this time I knew I wanted to learn how to do genetic studies and to discover genes.” With Prof. Lifton’s help Prof. Karet was awarded an intermediate fellowship from the Wellcome Trust for post-doctoral training in his Yale laboratory, which also gave her the opportunity to develop her own project. This focused on acid-handling by the kidney, rather than salt-handling (which is what underlies most of the blood pressure disorders), and she solved genetic puzzles in a rare inherited acid-handling disorder of the kidney. Prof. Karet said: “Your kidneys are like a washing machine, cleaning your blood day in, day out. When they start to fail, you will fall very ill and come under the care of a consultant – eventually most will need dialysis or a transplant. But the kidneys also play vital a housekeeping role, balancing the blood’s salt and acid (and other small molecule) levels. It is this ‘housekeeping’, and what happens if it goes wrong, which remains the focus of my research.” (Continued on p. 9) Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 8 Professor Fiona Karet (cont.) On her return to the UK, Prof. Karet was awarded a senior fellowship from the Wellcome Trust and opened her laboratory in the Cambridge Institute for Medical Research, where over the past 18 years her research team has moved from discovering a genetic disorder to trying to understand what that means in terms of physiology. Clinical service In 2005 Prof. Karet developed a multi-disciplinary clinical renal service in the hospital, including a clinical geneticist and urologist. The clinic looks after patients with inherited kidney disorders up until the point where they need dialysis or a transplant: “While their kidneys are still working I will be the person responsible for them in my clinical service. We’re very keen to provide advice to families of patients with genetic disorders, as they may also be at risk of the same condition. We can advise them on how they can manage lifestyles and diet, and often, offer a genetic test to give a yes/no answer to the question of risk. It’s very difficult having a rare disease, because you often feel as if you are the only person in the world who’s got it, so we find that people generally are very receptive to the engagement we offer them.” On alternate weeks the team sees patients with kidney stones who might have heritable disorders: “The urologist removes the stones and tells me what they’re made of, and we can then think about why the patients made them in the first place. Research “Research is fundamental to our service; we aim to recruit all our patients for potential research and where applicable encourage them to sign up to RaDaR [the National Registry of Rare Kidney Diseases]. We carry out a variety of clinical research with a different patient groups, including polycystic kidney disease (PKD) and cohorts of those with rarer disorders such as Gitelman’s Syndrome and UMOD (uromodulin) nephropathy, an inherited progressive disorder that leads to kidney failure”. From that work has come Prof. Karet's RD TRC-funded project on deep phenotyping and disease progression in patients within UMOD nephropathy. Industry collaboration RD-TRC is funding this clinical project, while a related project funded by Kidney Research UK and supported by a US company is looking at the basic science. The company provides the reagent for the team to use in their cellular experiments. Prof. Karet notes that working with industry is important: “Another interesting avenue we are just starting to develop concerns measuring devices for patients with electrolyte disorders, which would be open to commercial investment in the future.” Patient involvement Educating patients and clinicians is also important to Prof. Karet: “We have organised a number of patient/family support days for Gitelman’s and PKD, where patients can network with people who have the same condition and with doctors who have heard of their condition and are interested in them – they really respond to this. There is another day planned for October for Gitelman and Bartter Syndrome patients and their families, which will be RD TRC-funded. “The team is closely involved with the Patient-Led Research Hub at the Cambridge Clinical Trials Unit, with RaDaR and various patient-led groups. “Some of my patients have started fundraising to support our research and education activities. “It’s also important to educate providers of care and in July we held a rare renal disorders education day for people working in the multi-professional healthcare team.” (Continued on p. 10) Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 9 Professor Fiona Karet (cont.) The internet means that Prof Karet receives pleas for help and advice from patients all over the world: “I can’t help them directly because they are not my patients, but I’m always very happy to talk to their doctors and share experiences and knowledge of rare renal disorders – or their doctors are welcome to refer them! Funding landscape “The NIHR has done a fantastic job in recognising how important rare diseases are, because if you add up all the rare disease patients then you come to the equation that rare is common. “Unfortunately money is limited and post-BREXIT I’m afraid to say that the funding landscape is presently looking less certain. But we mustn’t lose sight of the fact that the healthcare professions and the research community are international – science should be global and it should be collaborative.” Rare Renal Disease Day An Account by Kathryn Irons On Friday July 1st 2016, Cambridge University Hospitals was host to 25 junior doctors and allied health professionals for an inaugural “Rare Renal Disease Day”. The day was designed to increase attendees' knowledge of rare renal conditions, and highlight advances currently being made and the importance of research. The day began with an informative talk from Professor Fiona Karet (RD-TRC Renal Theme Lead), highlighting lessons learned directly from patients with Rare Renal Disorders. Following on, Dr. Patrick Deegan (Addenbrooke's) gave an indepth presentation about Fabry’s Disease and how it affects the kidney. Fabry’s has very identifiable physical features and the audience examined how more educational events aimed at GP’s could help spread awareness and improve the speed at which patients are referred to hospital. Kathryn Irons, Theme Co-ordinator, supports Prof. Karet and the Renal Theme in the RD-TRC. If you have any questions regarding the Theme, please contact her via email: [email protected] After lunch, the audience was rewarded with an interesting and excellently presented talk about The Risk and Management of Thrombotic Microangiopathies (TMA) in the Organ Transplant Setting. Dr. Nick Torpey (Addenbrooke's) conveyed very complicated subject matter in a clear, concise way, allowing audience members unfamiliar with the area to follow the talk. Next, Dr. Danny Gale (UCL, Renal GeCIP Lead) provided a fascinating insight into Genomics and its future importance in helping to diagnose kidney disease. The day concluded with Dr. Tal Munir (Leeds) speaking on CKD in another ultra-rare rare disorder, paroxysmal nocturnal haemoglobinuria. Susana Borja Boluda, Addenbrooke's Rare Renal Research Nurse said “The day was very informative and interesting; a particular highlight was Professor Karet’s presentation at the start of the day. The location was good, the presenters were very approachable and friendly and there was lots of opportunity for discussion”. Carol Grenz, Living Donor Renal Transplant Coordinator added, “This was an informative day, which highlighted to me the importance of research in renal diseases, including in my specialist area. I learned that for example, research findings indicate that a renal condition (thin basement membrane disease) occasionally found in potential living kidney donors with microscopic amounts of blood in their urine and previously considered ‘benign’, may have to be taken more seriously. We are constantly learning more, moving forward in our understanding of rare renal conditions, developing new drugs and changing our practice to improve the lives of renal patients.” The day was co-sponsored by Alexion, Sanofi Genzyme and Shire. Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 10 Patient Day aims to help those who want to ‘Think Research!’ Two NIHR organisations involved in rare disease research have joined forces to organise a patient day, with the aim of involving patients more closely in their work. Taking place in London on 12 October, the Think Research! Patient Day is the brainchild of the NIHR Rare Diseases TRC and NIHR BioResource – Rare Diseases and is expected to attract 100-120 patients and their representatives. RD-TRC Operational Director Dr. Marijcke Veltman said: “Our aim for the day is to provide a tangible benefit to patients that we can measure and by offering training, which is free and relevant to patients interested in research, we believe we can achieve this. We want to know if patients take away and then apply the learning from our training to real-life examples; for example, have they joined steering committees, reviewed protocols or patient information leaflets, or set up their own patient support group website? From a purely RD-TRC perspective we would also like to see patients get to meet members of our Patient Advisory Group (PAG), and discover how they can liaise with them. The PAG acts as a conduit for the patient voice to our Strategic Oversight Group (SOG), and clearly the more patients who can be involved the more inclusive the PAG’s messages will be. To get meaningful data we will follow all our patients for the next 12 months so we can track trends and then fully evaluate the day’s success and decide whether it should be become an annual event.” Free training One of the big attractions of the day is the free training it will provide to patients. Delegates will be able to attend two out of four training sessions, facilitated by experienced trainers / advocates, over the course of the day, which will cover: • • • • Ethics Committees How to read study protocols Patient Information Leaflets / Sheets Running a successful patient group Speakers Speakers and facilitators include Simon Denegri, NIHR National Director for Patients and the Public in Research and Chair, INVOLVE, and Alastair Kent OBE, Director of Genetic Alliance UK and Chair of Rare Disease UK (RDUK). RD-TRC co-chair Professor John Bradley (RD TRC) and BioResource – Rare Diseases Director Professor Willem Ouwehand will give presentations on the future of rare disease research and the diagnostic odyssey, while Dr. Robert Semple and Professor Lucy Wedderburn will present on the metabolic and endocrine rare disease theme and childhood myositis respectively. Professor Adrian Thrasher will provide closing remarks. Expert Research Panel Facilitated by Alastair Kent, this will open discussions to the floor, looking at some of the research issues facing patients and support groups. Finally, there will be the opportunity to network with other patient support groups over lunch and discuss data and consent issues in greater detail with members of the RD-TRC data team in the bespoke ‘data corner’ that will be set up on the day. • Think Research! Patient Day will take place from 10am-4pm, Wednesday 12 October, at the Barbican Centre, London. If you are interested in finding out more please contact event organiser Georgina Norris T: 01223 254608 E: [email protected]. You can also find out more about the day on our website: rd.trc.nihr.ac.uk/think-research-patient-day/. Please note this event is by invitation only and you are advised to contact Georgina if you are associated with the two MINHR Organisations involved, would like to attend and have not yet received an invite. Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 11 Patient Day Programme A collaborative event between: Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 12 Eye Theme Update NIHR New Media Competition Winner Congratulations are in order for RD-TRC funded investigator, Dr. Mariya Moosajee who was the winner of the NIHR New Media Competition this year. The film entitled “Partnership for Sight” is narrated by and told through the perspective of Matthew Murrell, a patient taking part in Dr. Moosajee’s research. If you would like to view the video it can be found here: http://www.nihr.ac.uk/our-faculty/new-mediacompetition.htm Matthew describes the condition he lives with, choroideremia, and the change in vision that he has experienced which will eventually result in complete blindness. This research project has been taking skin cells from patients and converting them to retina cells, via initial conversion to stem cells, and investigating if a class of small molecule drugs can change the ‘stop’ signal in the defective gene to a ‘go’ signal. Matthew describes how taking part in this research has really given him hope that others like him may not have to face a future of complete blindness. Mariya and her team with the Director of Moorfields NIHR BRC, Professor Sir Peng Tee Khaw. Left to right: Maria Toms, Dhani Tracey-White, Mariya Moosajee, Peng Khaw, Rose Richardson & Matt Smart. The success of the study has enabled Dr. Moosajee to embark on an industry collaborative study with PTC Therapeutics and the RD-TRC, “Mapping the clinical phenotype of Choroideremia to identify an optimal therapeutic window for preventing sight loss – A UK multicentre deep phenotyping study”. Dr. Moosajee explains: “Choroideremia is a blinding genetic eye disease, where children develop night blindness and adults completely lose their vision. In order to progress from the laboratory to clinical trials we need to investigate the natural history of this disease and identify the best time to provide treatment to halt or slow the rate of sight loss”. The results of these studies may not only apply to patients with choroidermia but to other ophthalmologic rare diseases such as retinitis pigmentosa, Lebers congenital amaurosis and conerod dystrophies. PhD Secondment In parallel, Maria Toms has received £5,000 from the RD-TRC Eye Theme towards an international PhD secondment to the German Cancer Research Centre (DKFZ) in Heidelberg. Maria’s PhD involves characterising the retinal phenotype associated with USH2A, the most common causative gene associated with Usher syndrome, using various models including induced pluripotent stem cell derived retinal cells from affected patients. She is also focused on developing the use of non-viral gene therapy as a potential safe and therapeutic gene delivery strategy. Dr. Richard Harbottle leads the DNA Vector Research group at DKFZ and has expertise in generating novel next-generation DNA vectors, particularly the S/MAR vector system for in vivo application. During her time in Dr. Harbottle’s lab, Maria will learn the techniques involved in the production of these vectors and will generate USH2A-containing S/MARs that can be experimentally tested in an USH2A human cellular model to assess their safety and efficiency. S/MAR vectors offer great potential in providing treatments for many different rare genetic disorders that are due to the mutation of large genes. Patient Day Professor Graeme Black has started work on a patient day to be held in the autumn. ‘Rare Eye Disease Day’ will bring together patients and researchers from across the UK, showcasing updates on NIHR funded therapies and research on their associated conditions. In addition, patient focus groups will have their say on barriers to participating and being involved in research. Watch this space for more news and information. To register interest in the event please contact Theme Co-ordinator Kathryn Irons by email, [email protected], or telephone, 01223 245605, for more information. Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 13 RD-TRC Fellows’ Day 2016 The RD-TRC held its second Fellow's Day on July 26th, 2016 at Trinity Hall, University of Cambridge. The event was held to welcome our five newly appointed fellows to the larger team of researchers and staff. The day included a team building exercise for the first half of the day, which allowed the new fellows, the experienced fellows and RD-TRC support staff, to network and build contacts. The evening began with Professor Tim Barrett, Paediatric Theme Lead for the RD-TRC, addressing the fellows with poignant advice on how to develop your career in rare disease research and recounted some of his triumphs and stumbles along the way. Our Strategic Oversight Group, patient representative, the distinguished Alastair Kent, OBE, and Director of Genetic Alliance UK, discussed “Capturing the Patient Expertise in Translational Research” and stressed the importance on involving patients in research design and the benefits it. The evening included two talks by RD-TRC fellows who have been working on RD-TRC funded studies for the past two years. Dr. Ethan Sen, fellow in the Paediatric Theme, discussed steroid resistant nephrotic syndrome, his national cohort and the potential biomarkers he is aiming to define. Dr. Pedro Machado, fellow in the Muscle and Nerve Theme, presented an overview of his research programme in “Inclusion Body Myositis”. The reception to the Fellow’s Day has been very warm. Our feedback has been extremely positive and most fellows hope that we hold this event annually. We conducted a post event survey and requested feedback on the event itself and what fellows would like to see in the future from the RD-TRC. As a result, we are hoping to provide some additional courses that will address the gaps in research knowledge for some of the newer researchers. In the interim, Theme Co-ordinators and Data Co-ordinators are available to all fellows and researchers to offer hands-on help with document creation, ethics submissions, IRAS applications, HRA approval, so please get in contact if anything comes up. Yvonne Kamieniecka Senior Theme Co-ordinator Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 14 RD-TRC Fellows Introducing RD-TRC Research Fellows Dr. Christos Tziotzios Theme: Skin Diseases Supervisors: Prof. John McGrath Location: King’s College Hospital, London Project: Frontal fibrosing alopecia (FFA) is a highly distressing rare skin disorder associated with inflammation, scarring and irreversible hair loss. It is a rare disease affecting almost exclusively women, with an overall population prevalence of less than 1 in 10,000. The cause of FFA is unclear but there is evidence for a genetic contribution because it can run in some families. This project aims to discover the gene abnormality that causes FFA and what can be done to improve treatment or prevent the disease. Dr. Tziotzios will whole exome sequence a subset of participants alongside deep phenotype collection to draw genotype-phenotype correlations associated with the disease. A number of samples from this project were also sent for metabolomic analysis under the RDTRCs on-going collaboration with Metabolon. It is hoped this study will identify the causative genes of FFA and provide novel insight into important pathways involved in scarring, fibrosis and epithelial cell destruction. Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 15 The RD-TRC Data Co-Ordination Team Data Pipeline The Rare Disease TRD is continuing it’s objective in developing a rare disease database, and we are hoping to gain speed with the induction of two new data coordinators. Our new starters, John Li and Kimberley St.John-Green have joined mid-July and have already embedded themselves well into the team. We are currently advertising for a third Data Coordinator and are looking to recruit by the end of the summer. The new staff are currently undergoing training and sharing their skills with on-going studies. Our major obstacle in obtaining data from our studies appears to be a result of maintaining steady contact with the study teams. The Fellows Day held on 26th July was a step towards bridging gap. The day was both a fun and enriching experience for staff and fellows alike. The interactive activities helped to establish a better communication channel between the fellows and data coordinators, alike. We are hoping to follow through with further conversations with the fellows and to continue with regular updates regarding the studies. We have now gone live with 2 studies, (PaCiFy and PhenoDM1) and are hoping to follow shortly with the Childhood overgrowth disorders (POD) study. We’ll be contacting our newly appointed fellows soon, to begin the setup process of their studies in OpenClinca. Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 16 Introducing New Data Co-ordinators We would like to introduce two new members of the Data Team, here to help include in-depth phenotypic data into the OpenClinica database. John and Kimberley will work with investigators to design data plans and clinical record forms as well as facilitate the data inclusion. Welcome John and Kimberley! John Li Data Coordinator Tel: 01223 254627 Email: [email protected] John has a BSc in Computer Science and MSc in Computer Graphics and has previously been working the games industry as a games designer. He has been the NHS for just over a year as a Data Coordinator for Addenbrooke’s Paediatric Oncology & Haematology research team and has now joined the RD-TRC team Cambridge. in in at Kimberley St John-Green Data Coordinator Tel: 01223 254627 Email: [email protected] Kimberley received her Master’s degree in Chemistry from the University of York. She has worked in the Pfizer Institute of Pharmaceutical Materials Science modelling powder formulation for inhalation devices. Followed by working as a laboratory technician and administrator for Total Scientific Ltd., a contract research organisation at Babraham Research Campus. She has now joined as a clinical data coordinator at the RD-TRC. Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 IT 17 Cambridge Rare Disease Network (CDRN) Rare Disease Summit 2016 The Cambridge Rare Disease Network (CDRN; an organisation not formally linked to the RD-TRC) is hosting its second rare disease summit on 25 October in Cambridge. The summit will bring together international leaders in rare disease research and local experts to bridge the gap between research, industry, business and patient groups. The one-day conference will explore: • • • What can Cambridge contribute to global efforts in rare disease research? Who’s leading the way in collaborative, innovative research, treatment and care for those with rare diseases? How can we put patients and their families at the centre of all discussions? Confirmed speakers include: • EURORDIS CEO Dr. Yann Le Cam • Ben Howlett MP • Professor Patrick Maxwell, Regius Professor of Physic and Head of the School of Clinical Medicine of the University of Cambridge • Alastair Kent OBE, Genetic Alliance and Director of Rare Disease UK. Tickets for the CDRN Summit are now on sale through Eventbrite. To find out more visit: Eventbrite: eventbrite.co.uk/e/cambridge-international-rare-diseasesummit-2016-tickets-24888724846 Facebook: facebook.com/events/253880221626778/ Website: camraredisease.org Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 18 Forthcoming dates RD-TRC Research Symposium – II 15th September 2016 Trinity Hall, Cambridge Email: [email protected] Strategic Oversight Group - Meeting Dates 10th October 2016 10:00 – 15:00 RD-TRC Offices, Level 5, Barton House, Cambridge Biomedical Campus, CB2 0QQ RD-TRC & BioResource Rare Diseases THINK RESEARCH! Patient Day 12th October 2016 The Barbican Centre, London 10:00 – 16:00 A joint event with the NIHR BioResource - Rare Diseases to promote rare disease research and relevant research training to patients and their carers. Four training facilitators will provide hour-long training slots on different aspects of taking part in research. Simon Denegri, NIHR National Director for Patients & the Public in Research and INVOLVE Chair, and Alastair Kent, OBE, Director of Genetic Alliance UK, are keynote speakers. Email: [email protected] Patient Advisory Group Meeting Dates 16th November 2016 10:00 – 15:00 NCVO, 8 All Saints Street, London N1 9RL Theme Leads Meeting Dates 16 November 2016 13:00 – 16:00 NCVO, 8 All Saints Street, London N1 9RL 20th February 2017 13:00 – 16:00 (Venue TBC) London. Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 19 Forthcoming dates Forthcoming dates Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 21 Contact us NIHR Rare Diseases Translational Research Collaboration Barton House Level 5, Box 406 Cambridge Biomedical Research Campus Hills Road Cambridge CB2 0QQ UK Tel: 01223 254601 Website: http://rd.trc.nihr.ac.uk Rare Diseases Translational Research Collaboration Newsletter; Issue 14, August 2016 22