Predictive measures to stratify clinical outcomes in children and adults with Gaucher disease and responses to specific therapies

总体目标是改善戈谢病患者的管理。戈谢病是一种表现各异的遗传性疾病，但会导致致残疾病，尤其是骨骼致残，并影响大脑。生物技术的进步引入了特定的治疗方法：有四家公司生产的五种获得许可的疗法，它们以两种不同的方式起作用：以前使用骨髓移植（死亡率高）。尽管引进了这些高成本的治疗方法，但许多患者仍有持续的症状，并长期面临骨损伤、骨癌和帕金森病等脑部疾病的风险。造成这种情况的确切原因尚不清楚，但显然需要改进。为了实现我们的目标，我们将把位于高度专业化的国家中心的戈谢病治疗的主要从业人员聚集在一个综合研究联盟中。我们还将把来自学术机构和商业学术部门的临床科学家聚集在一起，通过更好的靶向治疗和治疗时机来改善治疗结果，并为设计特定试验建立一个起点，以努力改善戈歇患者的健康结果。我们与主要的工业合作伙伴密切合作，他们将把他们独特的专业知识与我们的临床和实验室工作相一致，整个项目将与该领域的患者倡导团体和国际协会合作。该联盟的许多具体科学工作将建立在一个综合数据库的基础上，该数据库反映了戈谢病在整个国家成人和儿童患者中的严重程度和表现。医学研究人员和专业护士将检查在道德上同意研究的个别患者，并从他们那里获得血液和其他适当的样本，并集中储存以供分析。数据资源将完全电脑化，这将使对疾病类别及其行为的复杂分析能够与通过实验室测量获得的有关该病的遗传学和其他变量的额外信息保持一致。将对患者进行重新检查，并回顾性地获取有关其疾病关键事件的临床信息，以便描述各种治疗前后的病程，并最终确定其特征。我们正在寻找对特定疗法反应良好或不太好的患者群体，他们的疾病进展可以被描述为“暴风雨”、“滋滋”或“滋滋”。我们已经有了一系列被批准的治疗方法（因为这是一种罕见的疾病，它们是“高成本”的），还有一系列被称为“生物标志物”的东西，这些东西很可能能够预测对治疗的反应，或者作为治疗控制疾病和不太可能发生并发症的目标。在与英国临床中心一起工作的研究小组中，有生物学家将探索这些生物标志物在疾病行为中的作用，以便改善治疗的靶向性，最佳使用时间，并在进一步的创新药物试验中改进疾病监测。通过这种方式，根据疾病严重程度和行为分层的患者群体“队列”将成为大型生物制药公司投资临床试验的有吸引力的平台。技术公司也将被吸引来开发诊断试剂盒，使用我们发现的生物标志物来改善预后。虽然罕见，但戈谢病有望对通常影响整个人群的鲜为人知的疾病提供独特的见解。大型企业（如赛诺菲）已被吸引到该领域，该财团的关键发现将在战略上吸引它们参与未来的投资和健康发展。

The overall aim is to improve the management of patients with Gaucher disease - a genetic disorder with very variable manifestations, but which causes disabling disease especially in the bones of the skeleton and affects the brain. Advances in biotechnology have introduced specific treatments: there are five licensed therapies manufactured by four companies which work in two distinct ways: formerly bone marrow transplantation (with high mortality) was used. Despite introduction of these high-cost therapies, many patients have persistent symptoms and suffer a long-term risk of bone injury, bone cancer and brain diseases such as Parkinson's. The exact reasons for this are unknown, but there is a clear need for improvement.To achieve our aim, we will bring key practitioners for the treatment of Gaucher disease, who are based in highly specialized national centres, together in a comprehensive research consortium. We will also bring clinical scientists from academic institutions and commercial academic sectors together in the mission to improve the outcomes of treatment by better targeting and timing of therapy, and to build a starting point for the design of specific trials in an effort to improve health outcomes for Gaucher patients. We work closely in the consortium with major industrial partners, who will bring their unique expertise in line with our clinical and laboratory work and the entire project will be partnered with patient advocacy groups and international societies in this field. Much of the specific scientific work of this consortium will be built on a comprehensive database reflecting the disease severity and manifestations of Gaucher disease in the entire national cohort of adults and children who suffer. Medical Researchers and specialized nurses will examine individual patients who have consented ethically to the study and from whom blood and other appropriate samples will be obtained and stored centrally for analysis. The data resource will be fully computerized, which will allow sophisticated analysis of the categories of disease and its behaviour to be aligned to additional information about the genetics of the condition and other variables obtained by laboratory measurement. The patients will be re-examined and clinical information obtained retrospectively about key events in their illness will be entered so that its course before and after various treatments can be described and, ultimately characterized. We are looking to define groups of patients who respond well or less well to specific therapies and whose disease progress can be characterized as 'stormy', 'sizzlers' or 'fizzlers'. We already have a range of treatments that have been authorized for prescription (because this is a rare disease they are 'high cost') and also a range of what are referred to as 'biomarkers' which may well be able to predict responses to treatment or serve as a target for when disease is controlled by therapy and complications are unlikely to occur. In the team of Investigators working alongside the UK clinical centres, there are biologists who will explore the role of these biomarkers in relation to disease behaviour so that the targeting of therapy, the best time to use it can be improved and that disease monitoring will be refined in further trials of innovative drugs. In this way, the groups 'cohorts' of patients stratified according to disease severity and behaviour will serve as an attractive platform for investment in clinical trials by the major biopharmaceutical companies. Technology companies will also be attracted to develop diagnostic kits using the biomarkers we discover to improve prognosis. Although rare, Gaucher disease promises unique insights into little-understood conditions that commonly affect the whole population. Large corporations (eg Sanofi) have been attracted to the field, and the key discoveries of the consortium will engage them strategically for future investment and health development.