Non-myeloablative conditioning with busulfan before hematopoietic stem cell transplantation leads to phenotypic correction of murine Bernard-Soulier syndrome.
Non-myeloablative conditioning with busulfan before hematopoietic stem cell transplantation leads to phenotypic correction of murine Bernard-Soulier syndrome.
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DOI：
10.1111/jth.12673
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发表时间：
2014-10
期刊：
影响因子：
--
通讯作者：
Shi Q
中科院分区：
文献类型：
--
作者：
Kanaji S;Fahs SA;Ware J;Montgomery RR;Shi Q
Bernard Soulier综合征（BSS）是一种以巨血小板减少为特征的遗传性出血性疾病。血小板输注用于出血管理，但重复输注往往导致同种异体免疫。我们最近已经证明了使用致死性辐射预处理，然后进行造血慢病毒介导的基因转移，对小鼠BSS（GPIbαnull）进行表型校正。为了将基因治疗应用于人类患者的治疗，重要的是使治疗相关的副作用最小化。本研究的目的是建立一个临床相关的非清髓性造血干细胞（HSC）移植策略模型。使用来自表达hGPIbα（hGPIbαtg+/+）的转基因小鼠的骨髓（BM）HSC移植，1）确定治疗获益所需的hGPIbαtg+/+ HSC百分比，2）评价使用白消安的非清髓性预处理的疗效，3）检测抗胸腺细胞球蛋白（ATG）预防/减少不良免疫应答的能力。将10- 20%hGPIb αtg+/+ BM HSC与GPIbαnull BM HSC混合移植到经辐照的GPIbαnull小鼠中足以校正出血时间（n = 5）。将hGPIbαtg+/+ BM HSC移植到白消安处理的GPIbα敲除小鼠中，27个受体中的21个校正了出血时间。在27只受体中的8只中记录了对hGPIbα的抗体应答和免疫介导的血小板减少症，表明白消安条件GPIbα裸小鼠中的hGPIbα具有免疫原性。然而，这些抗体在移植后30周内没有治疗就消失了。白消安加ATG预处理的组合成功地阻止了抗体的产生，并显著增加了治疗性植入。白消安与ATG联合预处理方案可能用于人类BSS的非清髓性自体基因治疗。
Bernard Soulier Syndrome (BSS) is an inherited bleeding disorder characterized by macrothrombocytopenia. Platelet transfusion is used for the management of bleeding but repeated transfusion often results in allo-immunization. We have recently shown phenotypic correction of murine BSS (GPIbαnull) using lethal radiation conditioning followed by hematopoietic lentivirus-mediated gene transfer. For application of gene therapy to treatment of human patients, it is important to minimize treatment-related side effects. The objective of this study is to model a clinically relevant non-myeloablative hematopoietic stem cell (HSC) transplantation strategy. Using transplantation of bone marrow (BM) HSCs from transgenic mice that express hGPIbα (hGPIbαtg+/+), 1) determine the percentage of hGPIbαtg+/+ HSCs required for therapeutic benefit, 2) evaluate the efficacy of non-myeloablative conditioning using busulfan, and 3) test the ability of anti-thymocyte globulin (ATG) to prevent/reduce undesirable immune responses. Transplantation of 10–20% hGPIbαtg+/+ BM HSCs mixed with GPIbαnull BM HSCs into irradiated GPIbαnull mice was sufficient to correct bleeding time (n = 5). Transplantation of hGPIbαtg+/+ BM HSCs into busulfan-conditioned GPIbαnull mice corrected bleeding time in 21 of 27 recipients. Antibody response to hGPIbα and immune-mediated thrombocytopenia was documented in 8 of 27 recipients, suggesting immunogenicity of hGPIbα in busulfan-conditioned GPIbαnull mice. However, these antibodies disappeared without treatment within 30 weeks after transplantation. A combination of busulfan plus ATG conditioning successfully prevented antibody development and significantly increased therapeutic engraftment. A conditioning regimen of busulfan in combination with ATG could potentially be utilized in non-myeloablative autologous gene therapy in human BSS.
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