A Novel Bone Marrow Transplantation Approach for Sickle Cell Disease Using Targeted Marrow Irradiation

项目摘要 镰状细胞病（SCD）是最常见的血液系统疾病，影响全球数百万人。 异基因造血细胞移植（HCT）是唯一的治愈性治疗，但与造血干细胞移植相关。 治疗相关器官毒性和移植物衰竭的显著风险。清髓性全身照射 (TBI)预处理促进完全植入，但其与较高的器官毒性相关。相反，减少 强度预处理与较少的器官毒性相关，但移植物排斥反应的风险较高，并且部分 在大多数情况下，用RIC获得的嵌合体不能解决血液学异常。因此 可以增加嵌合体同时降低方案相关毒性的预处理方案是一个未满足的需求， 治疗SCD。我们最近成功地治疗了我们的第一个SCD患者与图像引导全骨髓照射 (TMI)将6戈伊的辐射输送到骨髓（BM），同时将重要器官剂量限制在0-2戈伊， 随后是匹配的供体HCT，这导致完全嵌合，没有不良事件。然而， TMI后增强供体嵌合体的机制尚不清楚;强调临床前 问题研究我们已经开发出第一个临床前3D图像引导的TMI骨髓移植（BMT）模型， 使用免疫活性的C57 BL/6小鼠和人源化纯合BERK镰状小鼠（SS）。初步工作 提示基于TMI的骨髓靶向剂量递增在SCD小鼠模型中是可行的，支持 增加嵌合体和减少器官损伤。与杨森制药合作，我们将测试一种 血小板生成素（TPO）模拟药物（TPOm，又名JNJ-26366821），是一种完全合成的聚乙二醇化TPO 受体，c-MPL激动剂肽。TPOm的安全性已在I期临床试验中得到证明，正在II期 准备好了我们在小鼠模型中的初步数据表明，BMT后TPOm给药可增强HSC 再生，减轻辐射损伤，并支持血管再生。我们假设TMI- 基础剂量递增将促进植入（更高的归巢和嵌合），对其他细胞的毒性最小。 器官，从而改善SCD的病理生理学。我们进一步假设TPOm干预沿着 TMI将改善BM血管恢复、HSC扩张和植入。为了验证这个假设，我们将 在啮齿动物SCD模型中，使用以下方法优化BMT后的供体细胞归巢、植入和扩增 次级目标。我们将确定最佳的TMI剂量，以提高供体嵌合和完全植入， 减少溶血、贫血和组织损伤。我们将研究基于TMI的差异剂量递增 激活SDF-1梯度以支持增加供体细胞归巢至骨髓。调查是否添加 TPOm可通过增强BM血管恢复和供体HSC扩增来进一步改善植入。 我们的跨学科建议的总体目标是产生一个临床相关的，有效的，安全的TMI 剂量递增单独或与TPOm组合以改善嵌合和血管再生， 降低SCD HCT后的方案相关毒性。

PROJECT SUMMARY Sickle Cell Disease (SCD) is the most common hematologic disorder affecting millions of people worldwide. Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment but is associated with a significant risk of treatment-related organ toxicities and graft failure. While myeloablative total body irradiation (TBI) conditioning facilitates full engraftment, it is associated with higher organ toxicities. Conversely, reduced intensity conditioning is associated with less organ toxicities, but the risk of graft rejection is higher, and partial chimerism achieved with RIC cannot resolve the hematological abnormalities in most cases. Therefore, a conditioning regimen that can increase chimerism while lowering regimen-related toxicities is an unmet need to treat SCD. We recently successfully treated our first SCD patient with image-guided total marrow irradiation (TMI), delivering 6 Gy of radiation to the bone marrow (BM) while limiting the vital organ dose to 0-2 Gy, followed by matched donor HCT, which resulted in full chimerism without adverse events. Yet, the exact mechanism of the enhanced donor chimerism after TMI is not clear; emphasizing the need for preclinical studies. We have developed the first preclinical 3D image-guided TMI bone marrow transplant (BMT) model, using immunocompetent C57BL/6 mice and humanized homozygous BERK sickle mice (SS). Initial work suggests TMI-based bone marrow targeted dose escalation is feasible in the SCD mice model supporting increased chimerism and reduced organ damage. In collaboration with Janssen Pharmaceuticals, we will test a thrombopoietin (TPO) mimetic drug (TPOm, aka JNJ-26366821), which is a fully synthetic, PEGylated TPO receptor, c-MPL agonist peptide. The safety of TPOm has been proven in Phase I clinical trials and is phase II ready. Our preliminary data in a mouse model suggest post-BMT TPOm administration can enhance HSC regeneration, mitigate radiation damage, and support vascular regeneration. We hypothesize that the TMI- based dose escalation will facilitate engraftment (higher homing and chimerism) with minimal toxicities to other organs, resulting in improved pathophysiology of SCD. We further hypothesize that TPOm intervention along with TMI will improve BM vascular recovery, HSC expansion, and engraftment. To test the hypothesis, we will Optimize donor cell homing, engraftment, and expansion after BMT in a rodent SCD model using the following sub-aims. We will identify the optimal TMI dose to enhance donor chimerism and full engraftment which will reduce hemolysis, anemia, and tissue damage. We will investigate how TMI-based differential dose escalation activates SDF-1 gradient to support increasing donor cell homing to the bone marrow. Investigate if adding TPOm can further improve engraftment by augmenting BM vascular recovery and donor HSC expansion. The overarching goal of our interdisciplinary proposal is to produce a clinically relevant, effective, and safe TMI dose escalation alone or in combination with TPOm to improve chimerism and vascular regeneration while lowering regimen-related toxicities after HCT for SCD.