Induction of Stable Chimerism for Sickle Cell Anemia

造血细胞移植（HCT）对镰状细胞病患者具有治疗潜力。虽然常规HCT的结果良好，但这种治疗存在显著的短期和长期毒性风险。出于这个原因，HCT一直保留给那些经历过严重症状并预测预后不良的儿童。值得注意的是，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自然富集，即使有少数供体细胞，那些形成稳定嵌合体的人也具有显着的临床益处。这些观察结果为开发毒性较小、非清髓性的移植准备方案做出了巨大努力，首先在犬移植模型中得到证明，随后在患有血液恶性肿瘤的老年人的临床试验中成功转化。因此，基于这些支持性临床前和临床研究，该提案旨在研究用于镰状细胞病的改良移植程序，其显著降低HCT的毒性，但保留其治疗益处。这是一种新的方法，在门诊进行，这将依赖于建立和维持供体宿主嵌合体的能力。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后移植免疫抑制相结合来实现。这项研究将利用现有的镰状细胞和移植中心合作网络来识别和招募合格的患者。将确定稳定供体细胞植入的主要终点，并将随访测量对镰状细胞相关症状和终末器官损伤影响的次要终点。如果成功，这种新方法将扩大HCT对临床显著血红蛋白病患者的可用性。

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.