Severe Combined Immune Deficiency: Prospective and Longitudinal Study of Genotypes, Management and Outcomes

严重联合免疫缺陷：基因型、治疗和结果的前瞻性和纵向研究

• 批准号: 10250417
• 负责人: Christopher Craig Dvorak
• 金额: $ 7.46万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250417
• 关键词: Address; Age; Allogenic; Autologous; B-Lymphocytes; Biological Markers; Busulfan; CD4 Positive T Lymphocytes; Canada; Candidate Disease Gene; Cell Count; Cell physiology; Cells; Clinical; Clinical Trials; Cytomegalovirus; Cytomegalovirus Infections; Data; Data Set; Defect; Diagnosis; Disease; Disease Management; Disease-Free Survival; Dose; Drug Kinetics; Enrollment; Freedom; Future; Gene Expression Profiling; Genes; Genetic; Genotype; Grant; Hematopoietic; Human; Immune; Incidence; Individual; Infant; Infection; Intervention; Intervention Trial; Knowledge; Late Effects; Lesion; Longitudinal Studies; Lymphocyte Biology; Molecular Profiling; Mutation; Natural History; Neonatal Screening; Newly Diagnosed; Organ; Outcome; Outcome Assessment; Pathogenesis; Pathway interactions; Patient Outcomes Assessments; Patient-Focused Outcomes; Patients; Pharmacogenomics; Prevention trial; Procedures; Prospective Studies; Protocols documentation; Recovery; Research; Resources; Risk Factors; Severe Combined Immunodeficiency; Site; Survival Rate; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Thymus Gland; Translating; Transplantation; Variant; Virus Diseases; base; chemotherapy; cloud based; cohort; comparative; computational platform; conditioning; design; disease diagnosis; early detection biomarkers; exhaustion; follow-up; gene therapy; genetic variant; genome sequencing; health related quality of life; hematopoietic cell transplantation; immune reconstitution; infancy; novel; novel strategies; patient screening; prevent; prospective; randomized trial; side effect; therapy development; transplant survivor; transplantation therapy; treatment trial; whole genome

PIDTC Project 6907 SCID – Abstract Severe Combined Immunodeficiency Disease (SCID) is a genetically heterogeneous group of disorders leading to defects in T and B cell numbers or function. Our combined prospective (Protocol 6901) and retrospective (Protocol 6902) studies implemented during the 1st two grant cycles now include >750 surviving SCID patients, which will be further augmented with additional newly diagnosed patients from 44 US and Canadian PIDTC Centers during this grant cycle (Protocol 6907). Newborn screened (NBS) patients represent a high percentage of the SCID cohort, and now predominate in the USA and parts of Canada. Our prior studies have shown that: 1) ~7% of SCID cases have no identified genotype; 2) infection remains a major issue even in SCID diagnosed via NBS; 3) there are major gaps in our knowledge of hematopoietic cell transplant (HCT)- related late effects and health-related quality of life (HR-QoL); 4) while genotype strongly impacts overall survival (OS) and immune reconstitution, genotypic-specific approaches to optimize outcomes have not been defined; 5) CD4+ and naïve CD4+ T cell counts as early as 6 months post HCT predict long-term OS and immune reconstitution. These results have fueled the design and implementation of a prospective randomized trial exploring intensity of conditioning infants with SCID (NCT03619551). We propose that prospective enrollment of new cases plus extended follow-up of those previously enrolled will create an unparalleled resource for robust analysis of the SCID management and diagnosis approaches. While HCT treatment approaches are selected by individual centers, comprehensive, longitudinal data from this large PIDTC cohort will permit comparative assessment of outcomes beyond OS that will generate questions we will address in multicenter prospective SCID treatment trials. The objective of this proposal is to advance the understanding, diagnosis, management, and treatment of SCID in order to define how best to optimize survival and achieve full immune reconstitution after allogeneic HCT or autologous gene therapy (GT). With our large cohort we will: 1) identify unknown genes and functional defects in T cell development; 2) associate genotype and chemotherapy exposure in infancy with post-HCT late effects; 3) assess long-term outcomes of patients with SCID diagnosed by NBS and treated at a very young age (<6 months); 4) assess HR-QoL and patient reported outcomes (PROs); 5) further characterize the incidence and clinical associations of T cell exhaustion post- HCT, further defining early post HCT biomarkers to predict OS and immune reconstitution so that interventions can be designed to avoid rejection and/or enhance immune recovery; 6) determine which patients should receive GT with autologous modified hematopoietic cells, and 7) explore the incidence and reasons for pre- HCT viral infections in NBS SCID infants to propose clinical trials for prevention. The additional impact of the proposed research is that the longitudinal natural history and mechanistic studies we perform will generate hypotheses that translate into practice-changing clinical trials for SCID patients.

PIDTC项目6907 SCID-摘要 重症联合免疫缺陷病(SCID)是一组遗传上不同的疾病 导致T和B细胞数量或功能缺陷。我们的联合前景(6901号议定书)和 回顾(6902号议定书)在前两个赠款周期内实施的研究现在包括&gt；750个存活 SCID患者，将进一步增加来自44个美国和 加拿大PIDTC中心在此赠款周期内(6907号议定书)。新生儿筛查(NBS)患者代表 在SCID队列中的比例很高，现在在美国和加拿大的部分地区占主导地位。我们之前的研究 研究表明：1)~7%的SCID患者没有确定的基因；2)感染仍然是一个主要问题 通过国家统计局诊断的SCID；3)我们对造血细胞移植(HCT)的了解存在重大差距- 相关的后遗症和健康相关的生活质量(HR-QOL)；4)而基因对总体的影响很大 存活(OS)和免疫重建，基因特异性的方法来优化结果还没有 定义；5)早在HCT后6个月的CD4+和幼稚的CD4+T细胞计数就可以预测长期OS和 免疫重建。这些结果推动了前瞻性随机化的设计和实施 新生儿SCID条件化强度的初步探讨(NCT03619551)我们建议，未来 登记新病例，加上延长对先前登记病例的跟踪，将创造一个无与伦比的 对SCID管理和诊断方法进行稳健分析的资源。在进行红细胞压积治疗时 方法是由各个中心选择的，综合的、纵向的数据来自于这个庞大的PIDTC队列 将允许对操作系统以外的结果进行比较评估，这些结果将产生我们将在 多中心前瞻性SCID治疗试验。这项建议的目的是增进理解， SCID的诊断、管理和治疗，以确定如何最好地优化生存和实现 异基因HCT或自体基因治疗(GT)后完全免疫重建。在我们的庞大队伍中，我们将： 1)识别T细胞发育中的未知基因和功能缺陷；2)关联基因和 婴儿期化疗暴露与HCT后晚期反应；3)评估以下患者的长期结果 由国家统计局诊断并在非常小的年龄(6个月)接受治疗的SCID；4)评估HR-QOL并报告患者 结果(PRO)；5)进一步表征T细胞衰竭的发生率和临床相关性。 HCT，进一步定义HCT后早期生物标志物以预测OS和免疫重建，以便干预 可以设计为避免排斥和/或增强免疫恢复；6)确定哪些患者应该 用自体修饰的造血细胞接受GT，7)探讨Pre-Pre的发生率和原因 国家统计局SCID婴儿HCT病毒感染的预防建议临床试验。这一事件的额外影响 拟议的研究是我们进行的纵向自然历史和机制研究将产生 转化为改变实践的SCID患者临床试验的假设。