Novel curative therapies using genetic transfer of normal globin-producing genes into autologous hematopoietic stem cells (HSCs) are in clinical trials for patients with sickle cell disease (SCD). The percentage of transferred globin necessary to cure SCD is currently not known. In the setting of allogeneic nonmyeloablative HSC transplants (HSCTs), stable mixed chimerism is sufficient to reverse the disease. We regularly monitored 67 patients after HSCT. After initially robust engraftment, 3 of these patients experienced declining donor myeloid chimerism (DMC) levels with eventual return of disease. From this we discovered that 20% DMC is necessary to reverse the sickle phenotype. We subsequently developed a mathematical model to test the hypothesis that the percentage of DMC necessary is determined solely by differences between donor and recipient red blood cell (RBC) survival times. In our model, the required 20% DMC can be entirely explained by the large differences between donor and recipient RBC survival times. Our model predicts that the requisite DMC and therefore necessary level of transferred globin is lowest in patients with the highest reticulocyte counts and concomitantly shortened RBC lifespans.

中文翻译：

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至少 20% 的供体髓系嵌合体是逆转同种异体造血干细胞移植后镰状表型所必需的

使用正常珠蛋白产生基因遗传转移到自体造血干细胞 (HSC) 的新型治疗疗法正在临床试验中，用于治疗镰状细胞病 (SCD) 患者。目前尚不清楚治愈 SCD 所需的转移珠蛋白的百分比。在同种异体非清髓性 HSC 移植 (HSCT) 的情况下，稳定的混合嵌合体足以逆转疾病。我们在 HSCT 后定期监测 67 名患者。在最初稳健植入后，其中 3 名患者经历了供体骨髓嵌合 (DMC) 水平下降，最终疾病复发。由此我们发现 20% DMC 是逆转镰状表型所必需的。我们随后开发了一个数学模型来测试以下假设：必需的 DMC 百分比仅由供体和受体红细胞 (RBC) 存活时间之间的差异决定。在我们的模型中，所需的 20% DMC 可以完全由供体和受体 RBC 存活时间之间的巨大差异来解释。我们的模型预测，在网织红细胞计数最高并伴随红细胞寿命缩短的患者中，必需的 DMC 以及因此必需的转移珠蛋白水平最低。