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颖的个体化方法来理解和管理小儿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。威胁出血、贫血和感染。儿童 aAA 被认为是通过造血干细胞的免疫细胞攻击而发生的，但对其发病机制知之甚少，而且目前的治疗方法也不是基于机制的。一些 aAA 患者出现克隆性造血，这通常被悲观地视为即将发生骨髓增生异常或白血病的征兆。然而，情况可能并不总是如此，因为我们的初步研究已经发现许多患有克隆性造血的 aAA 患者多年来一直处于健康缓解状态。此外，许多患者的显性造血克隆中存在独特的突变。因此，我们假设 aAA 中的克隆造血是由突变事件引起的，这些突变事件赋予 HSC 或早期祖细胞生长或生存优势，特别是在面对与疾病相关的损伤时。我们将使用现代基因组方法来定义一大群 aAA 患者中这些突变的范围（目标 1），纵向跟踪患者的临床病程和遗传进化（目标 2），并研究与获得性 aAA 相关的功能后果通过基因操作和患者来源的诱导多能干细胞 (iPSC) 的体外造血分化来实现突变（目标 3）。我们研究的几个独特方面提高了其成功的可能性：首先，我们是一支由出色的研究人员组成的团队，在aAA、生物伦理学、基因组学/遗传学、造血和多能干细胞生物学的临床管理方面拥有广泛的协同专业知识。其次，M. Bessler（首席 PI）在费城儿童医院和宾夕法尼亚大学医院的综合性儿童-成人骨髓衰竭诊所对所有患者进行纵向跟踪。最后，我们的研究将利用 13 年来从 100 多名 aA 患者连续获得的大量临床注释良好的组织集合，其中包括 DNA 和冷冻保存的皮肤、血液和骨髓细胞。 Bessler 博士（首席 PI）将继续对这些患者进行临床跟踪，并在整个研究过程中获取更多样本。如果成功，我们的工作将确定一组基因和基因突变，对 aAA 进行分子分类，以更准确地预测预后，并确定更有效、基于机制的患者特异性疗法。