Targeted Improvement in Stem Cell Therapy for Leukemia and Bone Marrow Failure Sy

白血病和骨髓衰竭系统干细胞治疗的针对性改进

• 批准号: 8081967
• 负责人: QISHEN PANG
• 金额: $ 31.7万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8081967
• 关键词: Acute Myelocytic Leukemia; Adhesions; Biological Assay; Blood; Bone Marrow; Bone Marrow Transplantation; CD34 gene; Cell Adhesion; Cell Count; Cell Polarity; Cells; Clinical; Cyclophosphamide; Data; Defect; Disease; Disease model; Engraftment; Environment; Fanconi' s Anemia; Genetic; Goals; Grant; Healthcare; Hematological Disease; Hematopoietic; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homing; Human; Hypersensitivity; Image; Inflammatory; Inherited; Knock-out; Knowledge; Lead; Leukemic Hematopoietic Stem Cell; Life; Link; Mediating; Modeling; Mus; Pancytopenia; Patients; Population; Property; Regimen; Research Design; Second Primary Cancers; Signal Transduction; Stem cell transplant; Stem cells; Syndrome; Therapeutic; Tissues; Toxic effect; Transplantation; conditioning; congenic; fludarabine; gene correction; gene therapy; graft vs host disease; high risk; improved; in vivo Model; inhibitor/antagonist; innovation; irradiation; leukemia; migration; mouse model; mutant; novel; pre-clinical; preconditioning; primitive cell; progenitor; residence; rho GTP-Binding Proteins; stem; stem cell niche; stem cell therapy; success; two-photon

DESCRIPTION (provided by applicant): Fanconi anemia (FA) is a major inherited bone marrow (BM) failure syndrome with extremely high risk of developing acute myeloid leukemia (AML). The only curable treatment for this devastating disease is stem cell and gene therapies through BM transplantation. We recently described cell-autonomous defects of FA hematopoietic stem cells (HSCs) in BM homing and engraftment, and showed that these impaired functions were associated with a decrease in the activity of the Rho GTPase Cdc42 known to be essential for cell polarity, adhesion and migration. These results provide the first evidence for a missing link between FA deficiency and inefficient HSC engraftment. More recently, our preliminary studies show that genetic deletion of Cdc42 in mice causes massive mobilization of HSCs from BM niche. Furthermore, we have developed CASIN, a Cdc42 activity-specific inhibitor, which can specifically, transiently, and reversibly down regulate Cdc42 and Cdc42-regulated signaling activities, allowing successful engraftment of CD34+ human blood progenitors as well as transplanted congenic murine HSCs without myeloablative or irradiation preconditioning. Using a FA knockout (Fanca) mouse model we have shown that preconditioning of Fanca-/- mice with CASIN allows significant engraftment of WT or FANCA gene-corrected Fanca-/- HSCs in the absence of myeloablative or irradiation conditioning. These preliminary data suggest that Cdc42 controls HSC residence in the BM niche through regulating cell adhesion. We hypothesize that cell-autonomous defect of FA HSC engraftment is a direct consequence of decreased Cdc42 activity, a property that could be utilized to vacant BM niche otherwise occupied by mutant HSC or leukemic stem cells (LSCs) and allow wild-type or gene-corrected HSC to engraft. The goals of the project are to study the mechanism of Cdc42 targeting in the context of HSC mobilization and BM niche engraftment, and ultimately to develop a novel preclinical regimen by targeting Cdc42 to improve stem cell and gene therapies for leukemia and BM failure diseases, clinical settings in which intensive preconditioning and scarce stem cell numbers critically limit success. The project presents the first mechanistic study aimed at targeting a critical HSC-niche interaction regulator in a significant health-care setting. The knowledge gained from the proposed study will not only improve mechanistic understanding of stem cell mobilization and engraftment in the context of stem cell transplantation, but also lead to a new avenue of research designed to target Cdc42 for developing innovative therapeutic regimens for stem cell and gene therapies in leukemia and BM failure diseases. PUBLIC HEALTH RELEVANCE: Bone marrow transplantation (BMT) is the only curable treatment for certain devastating blood diseases such as leukemia and bone marrow (BM) failure syndromes. However, three major hurdles that have been hampering scientific and clinical advance in the BMT field: 1) ineffective mobilization of patient stem cells; 2) hypersensitivity of recipient patients to pre-conditioning regimens; and 3) inefficient delivery of genetically corrected patient stem cells to the BM niche. The goal of the project is to develop a novel preclinical regimen to improve BMT therapy for leukemia and BM failure diseases, clinical settings in which intensive preconditioning and scarce stem cell numbers critically limit success.

描述（由申请人提供）：Fanconi贫血（FA）是一种主要的遗传性骨髓（BM）衰竭综合征，患有急性髓样白血病（AML）的风险极高。这种毁灭性疾病的唯一可以治愈的治疗方法是通过BM移植进行干细胞和基因疗法。我们最近描述了BM归因和植入中FA造血干细胞（HSC）的细胞自主缺陷，并表明这些受损功能与Rho GTPase CDC42的活性降低有关，已知对细胞极性，粘附和迁移是必不可少的。这些结果为FA缺乏症与效率低下的HSC植入之间缺少联系提供了第一个证据。最近，我们的初步研究表明，小鼠中Cdc42的遗传缺失会导致BM利基市场大规模动员HSC。此外，我们开发了一种CDC42活性特异性抑制剂的赌场，可以具体，瞬时和可逆地调节CDC42和CDC42调节的信号传导活性，从而使CD34+人类血液祖细胞成功地植入了无骨含量或肌动型的先生性鼠HSC，而无需骨化的HSC。使用FA敲除（FANCA）小鼠模型，我们表明，在没有骨髓性或辐照调节的情况下，使用赌场对fanca - / - 小鼠的预处理可显着植入WT或Fanca基因校正的Fanca - / - HSC。这些初步数据表明，CDC42通过调节细胞粘附来控制BM生态位的HSC居住。我们假设FA HSC植入的细胞自主缺陷是Cdc42活性降低的直接结果，Cdc42活性降低，该特性可用于空置的BM利基，否则被突变的HSC或白血病干细胞（LSC）占据，并允许野生型或野生型或基因纠正的HSC来植入。 The goals of the project are to study the mechanism of Cdc42 targeting in the context of HSC mobilization and BM niche engraftment, and ultimately to develop a novel preclinical regimen by targeting Cdc42 to improve stem cell and gene therapies for leukemia and BM failure diseases, clinical settings in which intensive preconditioning and scarce stem cell numbers critically limit success.该项目介绍了旨在针对重要的HSC-NIHICHE相互作用调节器的第一项机械研究。从提议的研究中获得的知识不仅将在干细胞移植的背景下提高对干细胞动员和植入的机械理解，而且还导致了新的研究途径，旨在针对CDC42靶向用于开发白血病和BM衰竭疾病的干细胞和基因疗法的创新治疗方案。 公共卫生相关性：骨髓移植（BMT）是唯一可治愈某些毁灭性血液疾病（例如白血病和骨髓（BM）衰竭综合症）的治疗方法。但是，在BMT领域阻碍了科学和临床进展的三个主要障碍：1）无效动员患者干细胞； 2）接受者患者对预先调查方案的过敏性； 3）遗传校正的患者干细胞效率低下至BM生态位。该项目的目的是开发一种新型的临床前疗法，以改善白血病和BM衰竭疾病的BMT治疗，即临床环境，其中密集的预处理和稀缺的干细胞数量严重限制了成功。