Stem Cells as Delivery Vehicles and Imaging Probes for Glioma Gene Therapy

干细胞作为神经胶质瘤基因治疗的递送载体和成像探针

• 批准号: 7684237
• 负责人: ALI SYED ARBAB
• 金额: $ 19.58万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-08 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684237
• 关键词: Active Sites; Adjuvant Chemotherapy; Applications Grants; Area; Berlex brand of ferumoxides; Blood Vessels; Bone Marrow; Brain Neoplasms; Cells; Clinical; Detection; Diagnosis; Discipline of Nuclear Medicine; Endothelial Cells; Future; Gamma Cameras; Gene Delivery; Gene Transfer; Gene Transfer Techniques; Genes; Glioma; Goals; Growth; Harvest; Hematopoietic stem cells; Homing; Human; Hypoxia; Image; Imaging Techniques; Implant; Intra-Arterial Infusions; Intracranial Neoplasms; Invaded; Investigation; Label; Lymphoma; Magnetic Resonance; Magnetic Resonance Imaging; Magnetism; Malignant Glioma; Malignant neoplasm of lung; Mesenchymal Stem Cells; Methods; Modeling; Mutation; Nature; Neoplasm Metastasis; Nude Rats; Operative Surgical Procedures; Patients; Protamine Sulfate; Radiation therapy; Reporting; Research; Research Personnel; Resected; SLC5A5 gene; Site; Stem cells; System; Tc 99m-Pertechnetate; Technetium 99m; Techniques; Testing; Therapeutic; Transgenic Organisms; Translations; Transplantation; Tumor Angiogenesis; Tumor Tissue; Uncertainty; United States Food and Drug Administration; Xenograft procedure; angiogenesis; cell motility; chemokine; clinical application; ferumoxides; gene therapy; genetic manipulation; imaging probe; improved; in vivo; interest; iron oxide; magnetic field; migration; neoplastic cell; neovascularization; outcome forecast; peripheral blood; relating to nervous system; single photon emission computed tomography; sodium-iodide symporter; subcutaneous; success; therapeutic gene; treatment strategy; tumor; vector

DESCRIPTION (provided by applicant): Malignant gliomas are among the most devastating tumors, with survival only one to three years after diagnosis even with the best of treatments. Surgery and radiation therapy (followed by adjuvant chemotherapy), which form the standard practice, very often fail because of uncertainty in delineating the margin of the tumor. Moreover due to infiltrative nature of glioblastomamulteforme (GBM), it is not possible to resect 100% of tumor mass during surgery. Gene therapy promises to improve the prognosis of GBM, however, several factors including the lack of an efficient vector limit the ability of gene therapy to produce the desired success. Moreover, the vehicles for successful delivery of desired gene at desired site is still lacking. In recent years, different stem cells have been successfully employed to carry a gene to target tumor sites. The combination of gene transfer techniques with cellular transplantation is an elegant and promising approach to the delivery of therapeutic molecules to normal or neoplastic cells in the CNS. We have reported the ability of endothelial progenitor cells (EPCs), a class of hematopoietic stem cells, to migrate and incorporate into the angiogenesis of implanted glioma. EPCs have migrated actively at the periphery of the tumors when administered intravenously or locally and incorporated into angiogenesis. Detection of migration and incorporation was possible due to magnetic labeling of EPCs. These EPCs can be used as carrier as well as delivery vehicles for gene into tumors. Moreover, by magnetic labeling (using FDA approved ferumoxides and protamine sulfate); these cells can be used as cellular probes for MRI to track the movement of the cells after administration. Accessibility, easy harvesting and established techniques for genetic manipulation renders EPCs as attractive cellular vehicles when systemic gene carrier is required. In this proposed research, we aim to investigate the ability of EPCs to carry a gene to the tumor sites and use these transgenic cells as cellular probes to track the migration and incorporation in the tumors by magnetic resonance imaging (MRI). The goals of this research will be achieved by making glioma model in nude rats and magnetically labeled or unlabeled transgenic (carrying human sodium iodide symporter, hNIS) EPCs will be administered either systemically or locally, and the migration, homing and incorporation of these cells into tumor neovasculatures will be detected by MRI and nuclear medicine imaging technique (SPECT). If these cells carry and express hNIS at tumor sites (which will be detected by SPECT), it will open a new area of investigation with clinical applicability, where EPCs can be used as gene carrier or delivery vehicles. The long-term goal of this proposal is to extend the findings into clinical use by collecting stem cells from patients' peripheral blood and manipulate them as gene delivery vehicles for both systemic and local administrations, which can also be used as imaging probes for MRI.The results of this proposed project will advance the methods of diagnosis and treatment in two ways. Magnetically labeled cells will help detect the tumors using in vivo MRI by targeting active site of angiogenesis and this may help clinician to plan anti-angiogenic treatment strategy. If we are able to efficiently transfect and track the homing of these transgenic cells at the site of glioma, it will open a new way of delivering gene (for different factors) to the site of tumors using EPCs. Mixing magnetically labeled cells (for example 10% of total administered cells) with transgenic cells, MRI can also be used to confirm the migration and homing of transgenic cells at the sites of interest. Moreover, magnetically labeled transgenic cells can be delivered to a site of interest by applying external magnetic field during intra-arterial infusion.

描述（由申请人提供）：恶性胶质瘤是最具破坏性的肿瘤之一，即使采用最好的治疗，诊断后的生存期也只有一到三年。手术和放射治疗（其次是辅助化疗），这形成了标准的做法，往往失败，因为在划定肿瘤的边缘的不确定性。此外，由于多形性胶质母细胞瘤（GBM）的浸润性质，在手术期间不可能切除100%的肿瘤块。基因治疗有望改善GBM的预后，然而，包括缺乏有效载体在内的几个因素限制了基因治疗产生所需成功的能力。此外，仍然缺乏将所需基因成功递送至所需位点的载体。近年来，不同的干细胞已被成功地用于携带基因靶向肿瘤部位。基因转移技术与细胞移植的结合是一种将治疗分子递送到CNS中的正常或肿瘤细胞的优雅且有前途的方法。我们已经报道了内皮祖细胞（EPCs），一类造血干细胞，迁移和纳入植入胶质瘤的血管生成的能力。当静脉内或局部给药时，EPCs已在肿瘤周围积极迁移，并参与血管生成。由于磁性标记的EPCs的迁移和掺入的检测是可能的。这些内皮祖细胞可以作为基因的载体和传递工具进入肿瘤。此外，通过磁性标记（使用FDA批准的ferumoxides和硫酸鱼精蛋白），这些细胞可以用作MRI的细胞探针，以跟踪给药后细胞的运动。可获得性，易于收获和建立的遗传操作技术，使EPCs作为有吸引力的细胞载体时，需要系统的基因载体。在这项拟议的研究中，我们的目标是调查EPCs携带基因到肿瘤部位的能力，并使用这些转基因细胞作为细胞探针，通过磁共振成像（MRI）跟踪肿瘤中的迁移和掺入。本研究通过建立裸鼠胶质瘤模型，将磁标记或未标记的转基因（携带人钠碘转运体（hNIS））EPCs全身或局部给药，并通过MRI和核医学成像技术（SPECT）检测EPCs的迁移、归巢和掺入肿瘤新生血管的情况。如果这些细胞在肿瘤部位携带并表达hNIS（这将被SPECT检测到），这将开辟一个具有临床应用性的新的研究领域，其中EPCs可用作基因载体或递送载体。本项目的长期目标是，通过从患者外周血中提取干细胞，将其作为全身和局部给药的基因输送载体，并将其用作MRI的成像探针，从而将这一发现推广到临床应用。本项目的成果将从两个方面推进诊断和治疗方法。磁标记细胞将有助于使用体内MRI通过靶向血管生成的活性位点来检测肿瘤，这可能有助于临床医生计划抗血管生成治疗策略。如果我们能够有效地检测和跟踪这些转基因细胞在胶质瘤部位的归巢，这将开辟一条利用EPCs将基因（针对不同因子）递送到肿瘤部位的新途径。将磁性标记的细胞（例如总施用细胞的10%）与转基因细胞混合，MRI也可用于确认转基因细胞在感兴趣部位的迁移和归巢。此外，磁性标记的转基因细胞可以通过在动脉内输注期间施加外部磁场而递送到感兴趣的部位。