Reducing the Toxicity of BMT in Sickle Cell Anemia

描述(申请人提供)：该研究提案的主要目标是降低骨髓移植(BMT)治疗镰状细胞病(SCD)的毒性，以便将这一潜在的根治疗法推广到更多的患者。尽管有目前的治疗方法，但SCD与相当大的发病率和死亡率有关。清髓性骨髓移植可以治愈SCD，但其应用受到5-10%的死亡率、10%的失败率、移植物抗宿主病(GVHD)以及性腺和内分泌功能障碍风险的限制。非清髓性骨髓移植(NST)可导致混合造血嵌合体，供者和宿主骨髓稳定共存，且毒性可能低于清髓性BMT。由于正常红细胞(RBC)比镰状红细胞存活时间长得多，低水平的正常供者嵌合体可能会显著减少循环中镰状细胞的比例，并防止其病理效应。然而，在SCD患者中使用NST的经验有限。我们已经研究了混合嵌合体治疗SCD的动物模型，测试了诱导供者特异性耐受和减少GVHD的新的NST方案，并在SCD患者中进行了NST的临床试验。在接受治疗的7名患者中，有6名患者进行了最初的供体植入，毒性反应轻微且可逆，然而，所有患者都经历了晚期移植失败。我们现在假设，80%接受移植前氟达拉滨和低剂量全身照射(使用或不使用环磷酰胺(Cy)，移植后使用环磷酰胺、他克莫司和霉酚酸酯)的SCD患者将移植HLA相合的同胞骨髓。我们将研究体外抗供者反应性作为排斥反应的预测因子，追踪与移植和GVHD相关的其他因素，评估NST后的免疫重建，并评估这种治疗对多个临床参数的影响。我最近被招募到费城儿童医院，在BMT中建立一个非恶性疾病的临床研究计划，重点是SCD。我的目标是成为一名独立的临床科学家，通过获得正式指导并进行以患者为导向的研究，减少骨髓移植对SCD的毒性。我有一个强大的指导委员会，由具有临床试验开发、SCD、BMT、生物统计学、生物伦理学和移植生物学专业知识的科学家组成。作为培训的一部分，我将通过临床流行病学和生物统计中心获得临床研究硕士学位。

DESCRIPTION (provided by applicant): The main objective of the research proposal is to reduce the toxicity of bone marrow transplantation (BMT) for sickle cell disease (SCD) in order to extend this potentially curative therapy to more patients. Despite current therapies, SCD is associated with substantial morbidity and mortality. Myeloablative BMT can cure SCD but its application is limited by a 5-10% mortality risk, a 10% failure rate, graft-versus-host disease (GVHD) and the risk of gonadal and endocrine dysfunction. Nonmyeloablative BMT (NST) can result in mixed hematopoietic chimerism, stable co-existence of host and donor marrow, and may be less toxic than myeloablative BMT. Because normal red blood cells (RBCs) survive much longer than sickle RBCs, a low-level of normal donor chimerism may substantially reduce the fraction of sickle cells in the circulation and prevent their pathologic effects. There is limited experience, however, with NST in patients with SCD. We have studied animal models of mixed chimerism to treat SCD, tested novel NST regimens for inducing donor-specific tolerance and reducing GVHD, and piloted a clinical trial of NST in patients with SCD. Six of seven patients treated had initial donor engraftment and toxicities were mild and reversible, however, all patients experienced late graft failure. We now hypothesize that HLA-identical sibling bone marrow will engraft in >80% of patients with SCD who receive pre-transplantation fludarabine and low-dose total body irradiation, with or without cyclophosphamide (Cy), followed by post-transplantation Cy, tacrolimus and mycophenolate mofetil. We will study in-vitro anti-donor reactivity as a predictor of rejection, track other factors associated with engraftment and GVHD, assess immune reconstitution after NST, and evaluate the effect of this treatment on multiple clinical parameters. I was recently recruited to the Children's Hospital of Philadelphia to establish a clinical research program in BMT for non-malignant diseases, emphasizing SCD. My objective is to become an independent clinical scientist by obtaining formal instruction and conducting mentored patient-oriented research on reducing the toxicity of BMT for SCD. I have a strong mentoring committee composed of scientists with expertise in clinical trial development, SCD, BMT, biostatistics, bioethics and transplant biology. As part of my training, I will obtain a Master's Degree in Clinical Research through the Center for Clinical Epidemiology and Biostatistics.