Title: Understanding Genetic Causes of Cerebral Palsy: A Patient-Centric Approach to Improve Diagnosis and Develop New Treatments
Funder: Department of Health and Social Care

Abstract: Background Cerebral palsy (CP) is an early-onset life-long motor disorder occurring in the developing fetal or infant brain. It is one of the most commonly encountered neurological disorders of childhood, with an estimated UK incidence of 2.5/1000. A number of different motor patterns are described in CP, including spastic, hemiplegic, dystonic, dyskinetic, ataxic and hypotonic forms. CP is commonly associated with significant morbidity and mortality. The rising economic burden of CP is of significant global medical and socioeconomic concern.CP has been traditionally attributed to acquired brain injury and recognised risk factors include birth asphyxia, prematurity and low birth weight. Over time, it has become apparent that acquired injury accounts for only a proportion of patients with CP. In the current genomic era, an underlying genetic aetiology is identified in a significant number of children labelled as having CP. Indeed, in my pilot study of 95 cases, I established a genetic aetiology in 49 children, just over 50% of the cohort. For certain neurogenetic disorders, I have been able to instigate a personalized medicine approach leading to striking improvements in some patients. Gene identification can therefore have significant implications for accurate diagnosis, therapy, future prognostication, genetic counselling and medicolegal matters.Aims In this proposed NIHR Research Professorship, I aim to improve quality of life for patients with CP phenotypes. I will Establish genetic diagnoses for patients with CP phenotypes of suspected genetic origin Initiate gene-specific precision medicine strategies Develop guidelines to help clinicians both diagnose genetic forms of CP and manage these conditions Develop patient-derived neuronal models of disease to evaluate gene therapy and novel drug discovery Summary of Plan of Investigation At Great Ormond Street Hospital, I run a quaternary movement disorder service for children with complex motor disorders of undetermined aetiology. To date, I have recruited over 300 patients labelled as having CP but in whom I suspect an underlying genetic disorder. Following on from my successful pilot study, I plan to: Undertake genetic investigations in children with CP phenotypes in order to identify causative genes and new human diseases that mimic CP Confirm mutation pathogenicity where necessary through an established functional pipeline in my research laboratory Rapidly translate research findings into clinical practice by prompt addition of validated genes to NHS multigene panels and diagnostic exomes Develop consensus guidelines for investigating CP and managing genetic forms of CP Develop human induced pluripotent stem cells from patient fibroblasts for differentiation into neurons. These neuronal cell models of genetic CP will be ideal for drug discovery and evaluation of gene therapy strategies Summary of Potential Benefits to Patients and NHS My proposed fellowship will have clear rapid benefit to NHS patients. Gene discovery will aid accurate diagnosis, which can provide enormous relief for families, who have often had a difficult and tortuous diagnostic path. It can give families a sense of closure, allow prognostication and inform genetic counselling for future pregnancies. My research functional pipeline will further aid diagnostic certainty by determining the pathogenicity of novel, previously unreported variants. My work will also improve NHS diagnostic genetic testing as research genes will be rapidly translated into clinical practice by prompt addition to multigene panels and diagnostic exomes. My plan to develop consensus guidelines for genetic forms of CP will no doubt optimise patient diagnosis and treatment. Finally, gene discovery will facilitate a precision medicine approach for NHS patients, either through currently available therapies or through novel drug development. Using patient-derived neuronal cell models of genetic CP will be the perfect research platform to develop treatments for these neurological disorders.

Lay abstract: Background: Cerebral palsy is one of the commonest neurological disorders of childhood associated with significant disability. It can cause problems with movement and co-ordination, as well as with learning and behaviour. Although traditionally associated with birth injury, it is increasingly recognised that a significant number of children labelled as cerebral palsy have an underlying faulty gene causing their problems. This has important consequences, particularly with regard to establishing the correct answer for a child's condition, as well as ensuring that they have access to the best possible treatments.Work leading up to this proposal: Over the last decade, I have focused my research on establishing the underlying cause of disease in children with apparent cerebral palsy, in whom I clinically suspect an undiagnosed genetic condition. I have recruited patients into my study from my Specialist Movement Disorder Clinic at Great Ormond Street Hospital. These children have abnormal movements known as dystonia (abnormal repetitive twisting movements and postures), chorea (involuntary movements) and ataxia (unsteadiness). In this group of patients, I discovered a number of red flags which made me question whether these children really had classical cerebral palsy.In my preliminary genetic study of 95 patients, remarkably, I have identified a genetic cause in 49 cases, just over half of the children in this group. I have also identified particular treatments that benefit some patients with specific gene defects, a so-called precision medicine or personalised medicine approach. This has led to significant, often striking improvements in certain patients. Some disabled children have even regained the ability to walk independently.NIHR Research Professorship Aims, Design and Methods My overarching research aim is to improve the quality of life for NHS patients who have been labelled as having cerebral palsy. I plan to achieve this by: Improving diagnosis for patients: Through genetic research, I will identify the gene causing movement problems in children who have been labelled as having cerebral palsy. Where necessary, I will use established laboratory methods to prove that these genes are faulty, and have damaging effects which cause disease. This will provide families and children with proper answers, give much needed closure, negate the need for futher invasive investigations and help them make decisions about future pregnancies. Improving diagnosis within the NHS: Identified genes will be rapidly linked into NHS diagnostic laboratories to improve genetic testing more widely for NHS patients. Developing new treatments: For some genes, there may already be available treatments or strategies that I will implement for patients. For others, where there are currently no clearly effective treatments, I plan to use new state-of-the-art techniques to convert patients' skin cells into brain cells (neurons) to create a neuronal model which will provide me with an ideal system to test pioneering treatments, such as new drugs and gene therapy. Developing NHS guidelines: Not all patients with cerebral palsy need genetic testing. I will use my clinical expertise to develop guidelines that will help doctors and other healthcare professionals know when to undertake genetic testing in patients with cererbal palsy. I will also work closely with national and international researchers to develop recommendations for the management of these genetic conditions. Such guidelines will be published widely to help doctors accurately treat these genetic conditions that masquarade as cerebral palsy. I will engage with families and patient support groups who have significant insight into disease, and seek their invaluable assistance in guideline development. Patient and Public Involvment Already my patients, families and members of the public have heavily influenced my research by highlighting to me the important research questions that need to be answered. Many families have asked me Does my child really have cerebral palsy?, or are there better treatments for my child?. These key questions have formulated my research proposal. I wil continue to involve patients, families and the public in my research through active inclusion in my Research Steering Group and Patient Advisory Group. I plan regular open forums which will allow me to share research findings and discuss future strategies.Plans for Dissemination To ensure that all the right doctors, researchers and patients hear of this work, I will publicise research findings locally, nationally and internationally. I will publish work in open access (freely available) widely-read medical and scientific journals. Work will be presented at clinical meetings and scientific conferences, as well as to relevant patient support groups and charities. Research findings will be posted on appropriate websites linked to the University (UCL), NHS, charities and patient support groups.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL