Towards Precision Medicine in Childhood Acquired Aplastic Anemia

儿童获得性再生障碍性贫血的精准医疗

• 批准号: 9130826
• 负责人: STELLA T CHOU
• 金额: $ 56万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130826
• 关键词: Address; Adult; Anemia; Aplastic Anemia; Architecture; Area; Bioethics; Biology; Blood; Blood Cells; Bone Marrow; Bone Marrow Cells; CRISPR/Cas technology; Candidate Disease Gene; Caring; Cells; Characteristics; Child; Childhood; Clinic; Clinical; Clinical Management; Clinical Medicine; Clonal Evolution; Comparative Genomic Analysis; Constitutional; DNA; DNA Library; DNA Resequencing; Development; Diagnosis; Disease; Disease remission; Dysmyelopoietic Syndromes; Event; Evolution; Exhibits; Exposure to; Fibroblasts; Functional disorder; Gene Mutation; Genes; Genetic; Genomic approach; Genomics; Growth; Health; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemorrhage; Immune; In Vitro; Individual; Infection; Inflammatory; Inherited; Institutional Review Boards; Investigation; Lead; Life; Maps; Mediating; Monoclonal Antibody R24; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Outcome; Pancytopenia; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pediatric Hospitals; Pennsylvania; Philadelphia; Pluripotent Stem Cells; Predisposition; Production; Recovery; Research; Research Personnel; SNP array; Sampling; Science; Skin; Structure; Techniques; Technology; Testing; Time; Tissue Banks; Tissue Sample; Tissues; University Hospitals; Variant; Work; Zinc Fingers; base; clinically significant; cohort; cytokine; exome sequencing; genetic evolution; genetic manipulation; improved; individualized medicine; induced pluripotent stem cell; insight; leukemia; monocyte; multidisciplinary; novel; novel therapeutic intervention; outcome forecast; patient population; peripheral blood; personalized approach; personalized medicine; precision medicine; progenitor; repository; response; sample collection; skills; stem cell biology; success; tool; transcription activator-like effector nucleases; treatment response

DESCRIPTION (provided by applicant): Our multidisciplinary team of clinicians and researchers seeks novel patient-individualized approaches for understanding and managing pediatric acquired aplastic anemia (aAA), a rare but devastating condition characterized by bone marrow hematopoietic stem cell (HSC) hypoplasia with life threatening bleeding, anemia and infections. Pediatric aAA is believed to occur via immune cell attack of HSCs, but little more is known about the pathogenesis and current treatments are not mechanism-based. Some patients with aAA develop clonal hematopoiesis, which is typically viewed pessimistically as a sign of impending myelodysplasia or leukemia. However, this may not always be the case, as our preliminary studies have identified numerous aAA patients with clonal hematopoiesis who have been in healthy remission for years. Moreover, many of these patients harbor unique mutations within their dominant hematopoietic clones. Thus, we hypothesize that clonal hematopoeisis in aAA results from mutational events that impart a growth or survival advantage to HSCs or early progenitors, particularly in the face of disease-associated insults. We will use modern genomic approaches to define the scope of these mutations in a large cohort of aAA patients (Aim 1), follow the clinical course and genetic evolution of the patients longitudinally (Aim 2) and study the functional consequences of the aAA associated acquired mutations through genetic manipulation and in vitro hematopoietic differentiation of patient-derived induced pluripotent stem cells (iPSCs) (Aim 3). Several unique aspects of our study enhance its likelihood of success: First, we are a team of accomplished investigators with broad, synergistic expertise in the clinical management of aAA, bioethics, genomics/genetics, hematopoeisis and pluripotent stem cell biology. Second, M. Bessler (lead PI) follows all of the patients longitudinally in a comprehensive pediatric- adult bone marrow failure clinic at The Children's Hospital of Philadelphia and The Hospital of the University of Pennsylvania. Finally, our study will utilize a large clinically well-annotated tissue collection obtained serially from over 100 aA patients over 13 years, consisting of DNA and cryopreserved skin, blood and bone marrow cells. Dr. Bessler (lead PI) will continue to follow these patients clinically and procure additionl samples throughout the study. If successful, our work will identify sets of genes and gene mutations that will sub- classify aAA molecularly to predict prognosis more accurately and to identify more effective, mechanism-based patient-specific therapies.

描述（由申请人提供）：我们的多学科临床医生和研究人员团队寻求新的患者个性化方法来理解和管理儿科获得性再生障碍性贫血（aAA），这是一种罕见但具有破坏性的疾病，其特征是骨髓造血干细胞（HSC）发育不全，伴有危及生命的出血，贫血和感染。儿科aAA被认为是通过免疫细胞攻击HSC发生的，但对发病机制知之甚少，目前的治疗方法也不是基于机制的。一些aAA患者发生克隆性造血，通常被悲观地视为即将发生骨髓增生异常或白血病的迹象。然而，情况可能并非总是如此，因为我们的初步研究已经确定了许多具有克隆造血的aAA患者，这些患者多年来一直处于健康缓解状态。此外，这些患者中的许多人在其显性造血克隆内具有独特的突变。因此，我们假设aAA中的克隆造血是由突变事件引起的，突变事件赋予HSC或早期祖细胞生长或存活优势，特别是在面对疾病相关损伤时。我们将使用现代基因组学方法来确定这些突变在一个大型aAA患者队列中的范围（目标1），纵向跟踪患者的临床病程和遗传进化（目标2），并通过遗传操作和患者来源的诱导多能干细胞（iPSC）的体外造血分化研究aAA相关获得性突变的功能后果（目标3）。我们研究的几个独特方面增强了其成功的可能性：首先，我们是一个有成就的研究人员团队，在aAA的临床管理，生物伦理学，基因组学/遗传学，造血和多能干细胞生物学方面具有广泛的协同专业知识。第二，M。Bessler（PI负责人）在费城儿童医院和宾夕法尼亚大学医院的综合儿科-成人骨髓衰竭诊所纵向跟踪所有患者。最后，我们的研究将利用从100多名aA患者中连续获得的大量临床注释良好的组织收集，包括DNA和冷冻保存的皮肤，血液和骨髓细胞。Bessler博士（主要研究者）将继续对这些患者进行临床随访，并在整个研究期间采集额外样本。如果成功，我们的工作将确定基因和基因突变的集合，这些基因和基因突变将在分子上对aAA进行细分，以更准确地预测预后，并确定更有效的、基于机制的患者特异性疗法。