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: 6365241
• 负责人: Mark C Walters
• 金额: $ 48.91万
• 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/6365241
• 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）对于镰状细胞疾病的个体具有治愈的潜力。尽管常规HCT的结果很好，但这种治疗的风险却有显着的短期和长期毒性。因此，HCT已保留给患有严重症状的儿童，这些症状预测结果不佳。有趣的是，一些患者在常规HCT后出现了稳定的供体宿主造血嵌合体。由于血液中供体红细胞的天然富集，即使有少数供体细胞，也会产生稳定的嵌合体的人也具有显着的临床益处。这些观察结果与发展较低的，非毛刺性的制备机构进行移植的努力并行，在移植的犬模型中首次证明，随后在血液系统恶性肿瘤的老年人的临床试验中成功翻译了。因此，该提案基于这些支持的临床前和临床研究，旨在调查针对镰状细胞疾病的改良移植程序，该程序大大降低了HCT的毒性，但保留了其治疗益处。这是在门诊环境中进行的一种新颖方法，它将依靠建立和维持供体嵌合的能力。这将通过将毒性较小的，非肌瘤的移植前治疗与调节后的免疫抑制结合起来，旨在控制宿主 - 移植物和移植物旋转 - 抗宿主反应。这项调查将采用现有的协作镰状细胞和移植中心网络来识别和注册合格的患者。将确定稳定的供体细胞植入的主要终点，并将遵循对镰状细胞相关症状的影响的次要终点，并遵循最终器官损伤。如果成功，这种新颖的方法将扩大患有临床上显着血红蛋白病患者的HCT的可用性。