Facilitation of Autologous Hematopoietic Stem Cell Engraftment for Gene Therapy

促进自体造血干细胞移植用于基因治疗

• 批准号: 7404946
• 负责人: JULIAN DAVID DOWN
• 金额: $ 24.97万
• 依托单位: GENETIX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2010-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7404946
• 关键词: Ablation; Adverse effects; Animal Model; Animals; Area; Autoimmune Diseases; Autologous; Behavior Therapy; Biological Assay; Bioreductive Agent; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell; Bone Marrow Transplantation; Busulfan; Cell Therapy; Cells; Clinical; Clinical Trials; Condition; Cooley' s anemia; Cytotoxin; Development; Disease; Dose; Engraftment; Genes; Globin; Goals; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Hematopoietic stem cells; Hereditary Disease; Human; Hypoxia; Immune Tolerance; In Vitro; Lentivirus Vector; Liver; Lung; Malignant - descriptor; Malignant Neoplasms; Mediating; Methods; Mitosan; Modeling; Mus; Numbers; Organ; Oxygen measurement, partial pressure, arterial; Personal Satisfaction; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Property; Protocols documentation; Research Proposals; Schedule; Sickle Cell Anemia; Skin graft; Solid; Standards of Weights and Measures; Stem cell transplant; Stem cells; Thalassemia; Tissues; Toxic effect; Transgenes; Transplantation; Transplantation Conditioning; Treatment Protocols; Whole-Body Irradiation; analog; clinical application; concept; conditioning; gene therapy; improved; in vivo; irradiation; killings; research study; tirapazamine; tumor

DESCRIPTION (provided by applicant): Insufficient stem cell engraftment is a key problem that limits the application of transplant therapies for genetic and malignant diseases involving the hematopoietic system. Experimental studies have shown that depletion of primitive stem cells in the bone marrow is often required in the host before long- term engraftment from donor stem cells is achieved. In current clinical transplant protocols, this is usually accomplished using recipient conditioning with aggressive doses of whole body irradiation or busulfan. These treatments are limited by harsh side-effects. Recipient treatment with an agent capable of selectively depleting stem cells in the bone marrow microenvironment has the promise of providing less toxic and more specific replacement. Our goal in this phase I proposal is to demonstrate the proof of concept that these toxic treatments can be substituted by an agent that is specifically directed against the true hematopoietic stem cells (HSC) of the recipient by virtue of its existence in low oxygen tension. Such a strategy would allow the use of milder conditioning therapy in maximizing the engraftment of stem cells corrected by gene therapy in autologous transplants. Specifically, the initial development will comprise of administering tirapazamine (TPZ) and a closely related TPZ analog (SN 30000). We have already identified TPZ as being capable of depleting hypoxic bone marrow HSCs in the host and where we expect to achieve robust and persistent donor-type engraftment in murine recipients of syngeneic bone marrow. It is anticipated that we will identify an improved HSC transplant conditioning regimen that, together with the safe and effective means of delivering a gene therapy, can be extended to large animal models and eventually to human clinical application. Specific Aims: I. Optimize the bone marrow stem cell depleting properties of the hypoxia-selective cytotoxin tirapazamine (TPZ) and SN 30000; II. Assess the ability of these drugs to provide for long-term engraftment of normal donor stem cells in a bone marrow transplant model.7. Project Narrative Insufficient stem cell engraftment is a key problem that limits the application of transplant therapies for genetic and malignant diseases involving the hematopoietic system. Recipient treatment with an agent capable of selectively depleting stem cells in the bone marrow microenvironment has the promise of providing less toxic and more specific replacement for either irradiation or busulfan in stem cell-corrective gene therapy. We also expect that development of such a method will accelerate the clinical application of gene therapy directed at permanently correcting ?-thalassemia (Cooley's anemia) and sickle cell anemia which constitute some of most common and serious of the genetic diseases.

描述（由申请人提供）：干细胞植入不足是限制移植治疗涉及造血系统的遗传性和恶性疾病应用的关键问题。实验研究表明，在实现供体干细胞的长期移植之前，通常需要在宿主体内耗尽骨髓中的原始干细胞。在目前的临床移植方案中，这通常是通过全身照射或布硫凡的侵袭性剂量的受体调节来完成的。这些治疗受到严重副作用的限制。用一种能够选择性地消耗骨髓微环境中的干细胞的药物治疗受体，有望提供毒性更小、特异性更强的替代疗法。我们在这个I期提案中的目标是证明这些毒性治疗可以被一种药物替代，这种药物是专门针对受体的真正造血干细胞（HSC）的，因为它存在于低氧压下。这样的策略将允许使用温和的调理疗法，在自体移植中最大限度地通过基因疗法校正干细胞的植入。具体而言，最初的开发将包括给药替拉帕嗪（TPZ）和密切相关的TPZ类似物（SN 30000）。我们已经确定TPZ能够消耗宿主体内缺氧的骨髓造血干细胞，并且我们期望在同基因骨髓的小鼠受体中实现强大和持久的供体型植入。预计我们将确定一种改进的HSC移植调理方案，与安全有效的基因治疗方法一起，可以扩展到大型动物模型并最终应用于人类临床。1、优化低氧选择性细胞毒素替拉帕嗪（TPZ）和sn30000的骨髓干细胞消耗特性；2。评估这些药物在骨髓移植模型中提供正常供体干细胞长期植入的能力。干细胞植入不足是限制移植治疗涉及造血系统的遗传和恶性疾病应用的关键问题。在干细胞矫正基因治疗中，使用一种能够选择性地消耗骨髓微环境中的干细胞的药物对受体进行治疗，有望提供毒性更小、特异性更强的替代药物，以替代辐射或丁硫丹。我们还期望这种方法的发展将加速基因治疗的临床应用，以永久纠正？-地中海贫血（库利氏贫血）和镰状细胞性贫血，这是一些最常见和最严重的遗传性疾病。