Induction of Stable Chimerism for Sickle Cell Anemia

造血细胞移植（HCT）具有治疗个体镰状细胞病的潜力。虽然传统的HCT治疗效果良好，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一直保留给那些有严重症状的儿童，这些症状预示着预后不佳。有趣的是，一些患者在常规HCT后出现了稳定的供体-宿主嵌合。由于供体红细胞在血液中自然富集，即使供体细胞很少，嵌合稳定的患者也有显著的临床益处。这些观察结果与开发低毒性、非清髓性移植预备团的努力相一致，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转化。因此，本提案基于这些支持性的临床前和临床研究，旨在研究一种改良的镰状细胞病移植手术，该手术可显著降低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宿主嵌合的能力。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移植后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符合条件的患者。将确定稳定供体细胞移植的主要终点，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.