Gene-Engineered and Targeted Stem Cell Therapy for Myeloma

骨髓瘤的基因工程和靶向干细胞疗法

基本信息

批准号：
8450738
负责人：
Selvarangan Ponnazhagan
金额：
$ 27.43万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8450738
关键词：
Accounting Adjuvant Affect Angiogenic Factor Angiostatins B lymphoid malignancy Binding Biology Bone Diseases Bone Marrow Bone Pain Bone Resorption Bone remodeling Cell Proliferation Cell Therapy Cells Chemotherapy-Oncologic Procedure Clinical Trials Complement Factor B Development Disease Disease Management Disease Progression Disease remission Early treatment Ectopic Expression Endostatins Engineered Gene Event Gene Transfer Genetic Genetic Engineering Goals Growth Health Hematologic Neoplasms Homing Human Hypercalcemia Infiltration Integrins Lead Length Lesion Ligands Limb structure Long-Term Effects Lytic Marrow Mesenchymal Stem Cells Methods Modality Modification Molecular Morbidity - disease rate Multiple Myeloma Nuclear Osteoblasts Osteoclasts Osteolytic Pathological fracture Pathology Patients Pelvis Phase Plasma Cells Process Proteins Recombinant adeno-associated virus (rAAV)Recurrent disease Relapse Role Skeleton Staging Stromal Cells T-Lymphocyte TNFSF10 gene TNFSF11 gene Testing Therapeutic Therapeutic Effect Treatment Efficacy Treatment Protocols Tumor Angiogenesis Tumor necrosis factor receptor 11b Vascular Endothelial Growth Factors Work adeno-associated viral vector angiogenesis base bone bone loss cell growth chemotherapy cranium design disease diagnosis effective therapy gene therapy human disease improved in vivo inhibitor/antagonist long bone mouse model neoplastic cell novel osteoclastogenesis osteogenic osteopontin pre-clinical prevent receptor rib bone structure spine bone structure stem cell differentiation stem cell therapy tumor tumor growth tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Current advances in the treatment of multiple myeloma (MM) have resulted in a high rate of remissions; however, all patients eventually relapse and succumb to the disease. Cells in the bone marrow microenvironment are intimately involved in the disease process as regulators of myeloma growth and tumor manifestations. MM cells enhance bone resorption by triggering a coordinated increase in the receptor activator of nuclear factor-: B ligand (RANKL) and a decrease in osteoprotegerin (OPG) in the bone marrow. Further, osteoclasts enhance angiogenesis in concert with MM cells largely through the cooperative actions of osteopontin from osteoclasts and vascular endothelial growth factor (VEGF) from MM cells. The angiogenic effect further facilitates the vicious cycle between bone destruction and MM cell expansion. Thus, development of new, targeted therapies to abrogate key events of osteolytic bone destruction, MM cell growth and associated pathology of tumor angiogenesis, will lead to better management of the disease and increase patient survival. The overall goal of this proposal is to develop a new paradigm of myeloma therapy, whereby control of bone disease, tumor angiogenesis and tumor cells by targeted therapies to these events will help to control myeloma progression. We recently developed a novel method for bone enriched homing of genetically transduced MSC and demonstrated the potential of such MSC, modified to express OPG, in preventing osteolytic bone damage. Further, by using a recombinant adeno-associated virus vector (rAAV) encoding endostatin and angiostatin, we demonstrated significant delay in tumor growth and increase in long-term survival. In the proposed studies, we will determine the effects of these therapies in step-wise combination with chemotherapy in a mouse model of MM, which closely mimics the human disease pathology. The results of the proposed study will lead us to the next stage in which we will design treatment protocols aimed at improving myeloma-related bone disease and test treatment efficacy in preventing myeloma relapses and disease progression in human patients.

描述（申请人提供）：多发性骨髓瘤（MM）治疗的当前进展已导致较高的缓解率；但是，所有患者最终都会复发并屈服于该疾病。骨髓微环境中的细胞与骨髓瘤生长和肿瘤表现的调节剂密切相关。 MM细胞通过触发核因子的受体激活剂的协调增加来增强骨吸收 - B配体（RANKL）和骨髓中骨蛋白蛋白蛋白蛋白蛋白蛋白蛋白酶（OPG）的降低。此外，破骨细胞可通过从骨细胞和MM细胞的血管内皮细胞和血管内皮生长因子（VEGF）从骨桥蛋白的合作作用与MM细胞一起增强血管生成。血管生成效应进一步促进了骨骼破坏和MM细胞扩张之间的恶性循环。因此，开发新的有针对性疗法以消除骨质骨破坏，MM细胞生长以及肿瘤血管生成的相关病理学的关键事件，将导致更好地治疗该疾病并增加患者的生存率。该提案的总体目标是开发骨髓瘤疗法的新范式，从而通过针对这些事件的靶向疗法控制骨骼疾病，肿瘤血管生成和肿瘤细胞将有助于控制骨髓瘤进展。我们最近开发了一种新颖的方法，用于富含遗传转导的MSC的骨骼富集的归位，并证明了这种MSC的潜力，该MSC在防止骨化骨损伤方面进行了修改以表达OPG。此外，通过使用编码内抑素和血管抑素的重组腺相关病毒载体（RAAV），我们证明了肿瘤生长的显着延迟和长期存活率的增加。在拟议的研究中，我们将在MM的小鼠模型中确定这些疗法与化学疗法的逐步组合的影响，该模型紧密模仿了人类疾病病理学。拟议的研究的结果将使我们进入下一阶段，我们将设计旨在改善骨髓瘤相关骨病的治疗方案，并测试治疗疗效，以防止人类患者的骨髓瘤复发和疾病进展。