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: 6804660
• 负责人: Mark C Walters
• 金额: $ 55.07万
• 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 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6804660
• 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）对于镰状细胞病患者具有治疗潜力。虽然传统 HCT 的结果良好，但这种治疗存在显着的短期和长期毒性风险。因此，HCT 专门用于那些经历过严重症状（预示结果不佳）的儿童。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。由于血液中供体红细胞的自然富集，即使供体细胞很少，那些形成稳定嵌合体的人也具有显着的临床益处。这些观察结果与开发毒性较小、非清髓性移植准备方案的努力并行，首先在犬移植模型中得到证实，随后在针对患有血液恶性肿瘤的老年人的临床试验中成功转化。因此，该提案基于这些支持性临床前和临床研究，旨在研究一种改良的镰状细胞病移植手术，显着降低 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颖方法，它将依赖于建立和维持供体宿主嵌合状态的能力。它将通过将毒性较小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移植后免疫抑制相结合来实现。这项调查将利用现有的镰状细胞和移植中心协作网络来识别和招募符合条件的患者。将确定稳定供体细胞植入的主要终点，并跟踪测量对镰状细胞相关症状和终末器官损伤的影响的次要终点。如果成功，这种新方法将扩大 HCT 对临床显着血红蛋白病患者的可用性。

项目成果

Effect of myeloablative bone marrow transplantation on growth in children with sickle cell anaemia: results of the multicenter study of haematopoietic cell transplantation for sickle cell anaemia.

清髓性骨髓移植对镰状细胞性贫血儿童生长的影响：造血细胞移植治疗镰状细胞性贫血的多中心研究结果。

• DOI: 10.1111/j.1365-2141.2006.06486.x
• 发表时间: 2007
• 期刊: British journal of haematology
• 影响因子: 6.5
• 作者: Eggleston,B;Patience,M;Edwards,S;Adamkiewicz,T;Buchanan,GR;Davies,SC;Dickerhoff,R;Donfield,S;Feig,SA;Giller,RH;Haight,A;Horan,J;Hsu,LL;Kamani,N;Lane,P;Levine,JE;Margolis,D;Moore,TB;Ohene-Frempong,K;Redding-Lall
• 通讯作者: Redding-Lall