Title: A study to improve the diagnosis and understanding of the natural history of type I interferonopathies.
Funder: Department of Health and Social Care

Abstract: Background The pro-inflammatory cytokine type I interferon plays a key role in the innate immune response against viral infection. However, monogenic conditions associated with elevated levels of type I interferon and inflammatory disease are recognised and are collectively termed the type I interferonopathies. A wide variety of systems can be affected, with morbidity and mortality particularly associated with neurological, pulmonary and dermatological involvement. The prevalence of type I interferonopathies is unknown and diagnosis is often delayed or may be missed due to the extremely variable phenotype. It is likely that the full phenotypic spectrum associated with the type I interferonopathies has not yet been fully elucidated. Moreover, all current treatments in this grouping are supportive, but new treatment opportunities are on the horizon. As such there is a clear and urgent unmet clinical need for improved diagnosis and management. Research aims 1. Facilitate the diagnosis of type I interferonopathies. 2. Improve understanding of the disease phenotype associated with type I interferonopathies and thus enhance current medical care and future clinical trial design. Question to be addressed by this research Can the diagnosis and phenotypic understanding of type I interferonopathies be improved to benefit current medical care and future clinical trial design? Plan of investigation Aim 1 (Facilitate diagnosis) To improve recognition and offer access to expert clinical assessment I will undertake a clinic to review up to 48 individuals per year with a suspected type I interferonopathy. I will also offer advice and education to clinicians considering the diagnosis. I will arrange testing of interferon levels in English patients with suspected type I interferonopathies, as almost all molecularly-defined individuals identified to-date demonstrate persistently elevated levels in the blood (80 tests/year anticipated). Interferon levels will be assessed, in the research setting, by measuring the expression of down-stream interferon-stimulated genes. In patients with a clinically suspected interferonopathy and persistently elevated interferon-stimulated gene expression, diagnostic genetic testing of all known interferonopathy genes will be undertaken, using a virtual gene panel approach. Patients who are not diagnosed by this pathway will be offered entry into gene discovery research studies (within this study or through the 100,000 Genomes Project). Aim 2 (Enhance understanding of the disease phenotype) I will obtain ethics and approvals (prior to the Fellowship commencing) to undertake a natural history study of individuals with a molecularly-defined type I interferonopathy. Up to 36 patients will be reviewed annually, clinical data recorded and research samples collected for current and future studies. No such clinic has been established to date in England, or indeed the UK. I have access to 48 families who would be eligible for entry now. With consent, data will be collected from the clinicians of English patients who are unable to attend the clinic, to allow the aggregation and consolidation of information into one central repository. Potential benefits to patients and the NHS Improving the diagnosis of the type I interferonopathies is anticipated to benefit patients within two years and have a positive health care economic impact. An established diagnosis will abrogate the need for further diagnostic investigations and direct patient care. Prospective phenotyping will improve the understanding of disease manifestations, enhance patient management and allow guidelines to be created within five years. In addition it will help me to develop relevant outcome measures to reflect the clinical phenotypes seen in this population, which will be valuable in designing and conducting future interventional clinical trials. As interferon has a recognised role in the pathogenesis of more prevalent conditions, such as systemic lupus erythematosus and dermatomyositis, it is anticipated that the research findings will have clinical relevance to a wider patient group.CHAR(13) + CHAR(10)

Lay abstract: Aim of Research To improve the care of individuals with genetic disorders, which affect the immune system by: Facilitating earlier diagnosis Improving understanding of the problems caused by disease, to enhance current medical care and introduce treatments in England within the next five years This is important because these incurable disorders can cause serious disability and sometimes death in childhood. Background The immune system exists to fight infections that invade the body. The system is complex and involves many chemicals, including type I interferon. However, the system must be finely balanced as too much interferon can itself cause disease. Indeed, a change in one of several different genes can cause too much interferon to be produced, even when no infection is present. The problems that occur due to this differ depending upon which gene is changed, but frequently the result is devastating physical and mental disability. Caring for those affected by these diseases is difficult, because of limitations in our knowledge of the exact problems caused. Also, because the gene change may have been inherited, a couple may have other children or family members affected with the same condition. Early diagnosis and support is therefore key. At present there is no effective treatment for any of the diseases I study, but a number of possible treatments are on the horizon. Research planned to achieve aims Aim 1 (Facilitating earlier diagnosis) Making a diagnosis can be difficult because too much interferon can cause problems throughout the body such as severe learning difficulties, or lung disease needing transplantation affected individuals therefore often see many doctors. This frequently leads to a delay in diagnosis, or the diagnosis may not even be made. If we are to improve care we must ensure affected individuals are identified. I aim to improve this situation within two years, by: Running a specialist clinic to review individuals who may be affected and offer advice and education to doctors considering the diagnosis. Arranging testing of interferon levels on a national basis. A simple blood test can show if interferon levels are too high. If levels are consistently high, genetic testing may then be recommended. Introducing NHS genetic testing for all genes known to cause disease associated with too much interferon. Looking for new genes which cause disease in those individuals who are affected, but don't have a change in one of the genes already identified. Aim 2 (Enhancing medical care) Understanding the type of illnesses caused by too much interferon, will improve the care of affected individuals and their families within the next five years. The knowledge gained will also help identify which aspects of disease are best to monitor when treatments become available. I intend to improve understanding through recording the collective experience of the patient group, by: Setting up the first clinic in England to monitor individuals who have a gene change associated with too much interferon, on a yearly basis. Collecting clinical information from patients who cannot attend the clinic from their doctors. My training I will work with experienced research doctors, including those who are undertaking research overseas in a similar patient group, so that knowledge can be shared for greater patient benefit. I will undertake training to learn how to set up and run studies using new medicines (clinical trials). This will mean that when clinical trials start on these diseases in England, I will have the clinical expertise and research skills to lead such studies.Additional benefit Individually these genetic diseases are rare, but for the individuals affected, and also collectively, the burden of disease is great. Furthermore, there are common conditions associated with too much interferon production, particularly systemic lupus erythematosus and dermatomyositis, which can also cause severe problems throughout the body. It is therefore possible that the knowledge gained from my research will be of value to a wider patient group. Patient involvementMy research is informed by dialogue with patients with genetic and/or immune disease and their families. I will continue to involve the public in my research. For example, I will consult with patient groups about study leaflet design and run a focus group to discuss the research project. Dissemination I will communicate with patient groups, my University and NIHR media centres, and use online resources to ensure research findings are shared with the public. I will publish my findings, use established websites and speak at medical meetings to educate and update health care professionals.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION