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

• 批准号: 8247151
• 负责人: Selvarangan Ponnazhagan
• 金额: $ 29.18万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247151
• 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; Engineering; Event; Gene Transfer; Genetic; 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

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. PUBLIC HEALTH RELEVANCE: Multiple myeloma is a B-cell malignancy characterized by the infiltration and growth of plasma cells in the bone marrow. Patients with MM develop osteolytic bone disease permanently in the skull, ribs, vertebrae, pelvis, and long bones of the limb, characterized by bone pain, pathologic fractures, and hypercalcemia, making this a major cause of morbidity. Despite advances in chemotherapy regimens used to treat patients with MM, the median length of survival after diagnosis of the disease is approximately three years. Thus, newer therapies targeting multiple events of myeloma cell growth and proliferation, including bone microenvironment and tumor vasculature need to be developed for increasing patient survival. The central hypothesis of the proposed work is bone-targeted, genetically engineered MSC therapy capable of inhibiting osteoclast activity by stable expression of OPG will be an effective treatment for decreasing osteolytic bone lesions in MM. By combining the OPG therapy with tumor-targeted chemotherapy and tumor vasculature-targeted anti-angiogenic gene therapy we seek to establish a novel treatment paradigm for MM in a preclinical mouse model. Successful completion of these studies will allow us to initiate phase-1 human clinical trials.

描述（由申请人提供）：目前多发性骨髓瘤（MM）治疗的进展导致了高缓解率;然而，所有患者最终都会复发并死于该疾病。骨髓微环境中的细胞作为骨髓瘤生长和肿瘤表现的调节剂密切参与疾病过程。MM细胞通过触发骨髓中核因子受体活化剂：B配体（RANKL）的协同增加和骨保护素（OPG）的减少来增强骨吸收。此外，破骨细胞主要通过来自破骨细胞的骨桥蛋白和来自MM细胞的血管内皮生长因子（VEGF）的协同作用与MM细胞协同增强血管生成。血管生成作用进一步促进骨破坏和MM细胞扩增之间的恶性循环。因此，开发新的靶向治疗以消除溶骨性骨破坏、MM细胞生长和肿瘤血管生成的相关病理学的关键事件，将导致更好地管理疾病并增加患者存活率。该提案的总体目标是开发一种新的骨髓瘤治疗模式，通过针对这些事件的靶向治疗来控制骨疾病、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的方法，用于基因转导的MSC的骨富集归巢，并证明了这种MSC，修饰表达OPG，在预防溶骨性骨损伤的潜力。此外，通过使用编码内皮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著延迟和长期存活的增加。在拟定的研究中，我们将在MM小鼠模型中确定这些疗法与化疗逐步联合的效果，该模型密切模拟人类疾病病理学。拟议研究的结果将引导我们进入下一阶段，在该阶段，我们将设计旨在改善骨髓瘤相关骨病的治疗方案，并测试治疗在预防人类患者骨髓瘤复发和疾病进展方面的疗效。公共卫生相关性：多发性骨髓瘤是一种B细胞恶性肿瘤，其特征是骨髓中浆细胞的浸润和生长。MM患者在颅骨、肋骨、椎骨、骨盆和四肢长骨中发生永久性溶骨性骨病，其特征为骨痛、病理性骨折和高钙血症，使其成为发病的主要原因。尽管用于治疗MM患者的化疗方案取得了进展，但诊断后的中位生存期约为3年。因此，需要开发针对骨髓瘤细胞生长和增殖的多种事件（包括骨微环境和肿瘤血管系统）的更新疗法，以提高患者的生存率。该研究的中心假设是骨靶向的基因工程MSC治疗能够通过稳定表达OPG抑制破骨细胞活性，将是减少MM溶骨性病变的有效治疗方法。通过将OPG治疗与肿瘤靶向化疗和肿瘤血管靶向抗血管生成基因治疗相结合，我们寻求在临床前小鼠模型中建立MM的新治疗模式。这些研究的成功完成将使我们能够启动1期人体临床试验。