Targeting Leukemic Stem Cells

靶向白血病干细胞

基本信息

批准号：
8113184
负责人：
DANIEL G TENEN
金额：
$ 41.93万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-25 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8113184
关键词：
Accounting Antibodies Apoptosis Binding Biological Assay Biology Blast Phase Blood CD34 Antigens CD34 gene Cell Count Cell Cycle Cell Line Cell physiology Cells Characteristics Chemotherapy-Oncologic Procedure Chronic Myeloid Leukemia Clinical Trials Complex DNA Dependence Development Disease Drug Kinetics Drug resistance Engineering Failure Gene Abnormality Gene Expression Gene Transduction Agent Genes Goals Hematological Disease Hematopoietic stem cells Human In Vitro Laser Scanning Cytometry Lead Left Leukemic Cell Malignant - descriptor Malignant Neoplasms Mediating Methods Modeling Mus Myelogenous NOD/SCID mouse Oncogenes Organ Patients Population Property Protamines Proteins RNA Recombinants Relapse Research Resistance development Route Safety Sampling Small Interfering RNA Specificity Staging Stem Cell Factor Stem cells Surface System Systems Development Testing Time Tissues Transgenic Mice Treatment Failure Viral Vector Xenograft procedure antigene base bcr-abl Fusion Proteins cancer cell cancer stem cell cancer therapy cell growth cell type dosage effective therapy embryonic stem cell gene therapy human stem cells in vivo in vivo Model leukemia mouse model non-viral gene therapy novel prevent protein expression reagent testing research study self-renewal therapy development tumor

项目摘要

DESCRIPTION (provided by applicant): Although advances in our understanding of gene abnormalities in diseases involving blood organs and other tissues has been remarkable in recent years, the ability to introduce or manipulate expression of genes in target cells through gene therapy methods has been limited. Although a number of powerful viral vectors have been developed and utilized in both experimental and human systems, a number of issues, particularly safety, have demonstrated the need to develop non-viral based vectors for gene therapy. Recent discoveries have also demonstrated that it is essential to target normal hematopoietic stem cells (HSC), cells which have the potential to both self-renew and to give rise to all cell types in a given tissue, as well as leukemic stem cells (LSC), a subpopulation of cancer cells which confer the self-renewal properties of the malignant leukemic clone. Normal human HSC, and a majority of LSC, express the stem cell antigen CD34, and this proposal will utilize the specificity of this surface marker, as well as a novel murine model in which murine HSC express the human CD34 antigen. Therefore, the long range goals of this project are to develop novel non-viral gene therapy methods targeting normal and leukemic stem cells. In order to accomplish these goals, we propose the following Specific Aims: (1) to test human CD34 antibody mediated siRNA delivery in human CD34 cell lines; (2) to test human CD34 antibody mediated siRNA in murine models in vivo; and (3) to test whether human CD34 antibody mediated silencing of BCR/ABL or SALL4 will inhibit proliferation and leukemia-initiating ability of human primary myeloid LSCs. Accomplishment of these goals will set the stage for clinical trials, as well as lead to development of therapies directed against other oncogenes as well as altering stem cell gene expression.

描述（由申请人提供）：尽管近年来我们对涉及血液器官和其他组织的疾病的基因异常的理解取得了显着的进步，但通过基因治疗方法在靶细胞中引入或操纵基因表达的能力仍然有限。尽管已经开发出许多强大的病毒载体并在实验和人体系统中使用，但许多问题，特别是安全性，已经表明需要开发基于非病毒的基因治疗载体。最近的发现还表明，针对正常造血干细胞 (HSC) 以及白血病干细胞 (LSC) 至关重要，正常造血干细胞具有自我更新和在给定组织中产生所有细胞类型的潜力。），癌细胞的一个亚群，赋予恶性白血病克隆的自我更新特性。正常人类 HSC 和大部分 LSC 表达干细胞抗原 CD34，该提案将利用这种表面标记的特异性，以及一种新型小鼠模型，其中小鼠 HSC 表达人类 CD34 抗原。因此，该项目的长期目标是开发针对正常和白血病干细胞的新型非病毒基因治疗方法。为了实现这些目标，我们提出以下具体目标：（1）在人CD34细胞系中测试人CD34抗体介导的siRNA递送； (2) 在小鼠模型中体内测试人CD34抗体介导的siRNA； (3) 测试人 CD34 抗体介导的 BCR/ABL 或 SALL4 沉默是否会抑制人原发性骨髓 LSC 的增殖和白血病起始能力。这些目标的实现将为临床试验奠定基础，并导致针对其他癌基因以及改变干细胞基因表达的疗法的开发。