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

总体目标是改善对高谢病患者的管理。高谢病是一种遗传性疾病，表现非常多样，但会导致致残性疾病，特别是骨骼疾病，并影响大脑。生物技术的进步带来了特定的治疗方法：四家公司生产了五种获得许可的治疗方法，它们以两种不同的方式发挥作用：以前使用的是骨髓移植(死亡率很高)。尽管引入了这些昂贵的治疗方法，但许多患者仍有持续的症状，并面临骨损伤、骨癌和帕金森氏症等脑部疾病的长期风险。确切原因尚不清楚，但显然需要改进。为了实现我们的目标，我们将把治疗高谢病的关键从业者聚集在一个综合研究联盟中，他们设在高度专业化的国家中心。我们还将把学术机构和商业学术部门的临床科学家聚集在一起，通过更好的靶向和治疗时机来改善治疗结果，并为具体试验的设计建立一个起点，以努力改善高谢尔患者的健康结果。我们与主要行业合作伙伴在该联盟中密切合作，这些合作伙伴将把他们独特的专业知识与我们的临床和实验室工作结合起来，整个项目将与患者权益倡导团体和这一领域的国际社会合作。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，该数据库反映了整个国家成人和儿童队列中高谢病的严重程度和表现形式。医学研究人员和专门护士将检查在道德上同意这项研究的个别患者，并从他们那里获取血液和其他适当的样本，并将其集中存储以供分析。数据资源将完全计算机化，这将使对疾病类别及其行为的复杂分析与通过实验室测量获得的关于病情遗传和其他变量的更多信息保持一致。患者将被重新检查，并将回顾获得的有关其疾病关键事件的临床信息输入，以便描述其在各种治疗前后的过程，并最终确定其特征。我们希望定义对特定治疗反应好或不好的患者群体，他们的疾病进展可以被描述为“暴风雨”、“嘶嘶声”或“嘶嘶声”。我们已经有一系列的治疗方法被授权开出处方(因为这是一种罕见的疾病，他们的成本很高)，还有一系列被称为生物标记物的药物，它们很可能能够预测治疗的反应，或者成为疾病通过治疗控制且不太可能发生并发症时的目标。在与英国临床中心合作的研究团队中，有生物学家将探索这些生物标记物在疾病行为中的作用，以便改善治疗的靶向性，改善使用它的最佳时间，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将成为主要生物制药公司投资临床试验的有吸引力的平台。科技公司也将被吸引到使用我们发现的改善预后的生物标志物来开发诊断试剂盒。虽然罕见，但高谢病对通常影响整个人群的鲜为人知的疾病提供了独特的见解。大公司(如赛诺菲)已被吸引到该领域，该财团的关键发现将使它们在未来的投资和健康发展方面具有战略意义。

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.