Induction of Stable Chimerism for Sickle Cell Anemia

镰状细胞性贫血稳定嵌合体的诱导

• 批准号: 6527795
• 负责人: Mark C Walters
• 金额: $ 52.09万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-25 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6527795
• 关键词: African American; T lymphocyte; biomarker; bone marrow purging; child (0-11); cooperative study; cytotoxicity; enzyme linked immunosorbent assay; flow cytometry; fludarabine; graft versus host disease; hematopoietic tissue transplantation; histocompatibility; human subject; immunosuppression; leukocyte activation /transformation; patient oriented research; radiation therapy; sickle cell anemia; sign /symptom; stem cell transplantation; tissue /cell culture; tissue mosaicism; transplant rejection; transplantation immunology

Hematopoietic cell transplantation (HCT) has curative potential for individuals with sickle cell disease. While the results of conventional HCT have been good, this treatment carries risks of significant short- term and longterm toxicities. For this reason, HCT has been reserved for children who have experienced severe symptoms that predict a poor outcome. Of interest, some patients developed stable donor-host hematopoietic chimerism after conventional HCT. Due to a natural enrichment of donor erythrocytes in the blood, those who developed stable chimerism had a significant clinical benefit, even when there was a minority of donor cells. These observations have paralleled efforts to develop less-toxic, non-myeloablative preparative regiments for transplantation, proved first in a canine model of transplantation, and subsequently translated successfully in a clinical trial for older adults with hematological malignancies. Thus, this proposal, based on these supporting pre-clinical and clinical investigations, aims to investigate a modified transplant procedure for sickle cell disease that significantly reduces the toxicity of HCT, yet retains its therapeutic benefit. This is a novel approach, conducted in the outpatient setting, which will rely upon the ability to establish and maintain donorhost chimerism. It will be achieved by combining less toxic, non-myeloablative pre-transplant therapy with modulated post-grafting immuno-suppression aimed at controlling host-versus-graft and graft-versus-host reactions. This investigation will employ an existing network of collaborative sickle cell and transplant centers to identify and enroll eligible patients. The primary endpoint of stable donor cell engraftment will be determined and secondary endpoints to measure the impact on sickle cell-related symptoms and end-organ damage will be followed. If successful, this novel approach will expand the availability of HCT for patients with clinically significant hemoglobinopathies.

造血细胞移植(HCT)对镰状细胞病患者有治疗潜力。虽然常规HCT的结果很好，但这种治疗存在严重的短期和长期毒性风险。出于这个原因，HCT一直被保留给那些经历了严重症状并预示着不良结局的儿童。有趣的是，一些患者在常规HCT后出现了稳定的供者-宿主造血嵌合体。由于供者红细胞在血液中的自然丰富，那些发展出稳定嵌合体的人有显著的临床益处，即使有少数供体细胞。这些观察结果与开发毒性较低、非清髓性的移植准备方案的努力是平行的，该方案首先在犬移植模型中得到证实，随后在患有血液系统恶性肿瘤的老年人的临床试验中成功翻译。因此，基于这些支持的临床前和临床研究，这项建议的目的是研究一种改良的镰状细胞病移植程序，显著降低HCT的毒性，同时保留其治疗益处。这是一种在门诊环境中进行的新方法，它将依赖于建立和维持供体嵌合体的能力。这将通过将毒性较低的非清髓性移植前治疗与旨在控制宿主抗移植物和移植物抗宿主反应的调节性移植后免疫抑制相结合来实现。这项调查将利用现有的协作镰状细胞和移植中心网络来识别和登记符合条件的患者。将确定稳定的供体细胞移植的主要终点，随后将确定次要终点，以衡量对镰状细胞相关症状和末端器官损害的影响。如果成功，这一新的方法将扩大HCT的可用性，用于临床上有重要意义的血红蛋白疾病患者。