Therapeutic expression of the platelet-specific integrin, αIIbβ3, in a murine model for Glanzmann thrombasthenia
Therapeutic expression of the platelet-specific integrin, αIIbβ3, in a murine model for Glanzmann thrombasthenia
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DOI：
10.1182/blood-2004-12-4619
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发表时间：
2005-10-15
期刊：
影响因子：
20.3
通讯作者：
Wilcox, DA
中科院分区：
文献类型：
--
作者：
Fang, J;Hodivala-Dilke, K;Wilcox, DA
在发育、免疫、转移、血栓形成和伤口愈合过程中，整合素介导细胞之间和细胞外基质的粘附。-或-亚基的分子缺陷可破坏整合素的合成、组装和/或与粘附配体的结合。出血性疾病Glanzmann血栓减少症（GT）就是例证，其中血小板特异性整合素α IIb β 3的异常阻止了血管损伤后的血小板聚集。我们之前使用含有编码人类整合素β 3的cDNA盒的逆转录病毒载体来恢复来自GT患者外周血干细胞的巨核细胞表面的整合素α IIb β 3。本研究用ITG β 3-cassette转导β 3-缺失小鼠骨髓，观察血小板后代是否能在体内建立止血作用。配备人ITGA2B基因启动子的慢病毒转移载体将转基因表达限制在血小板谱系中。人β 3与小鼠α IIb形成稳定复合物，有效恢复血小板功能。在循环血小板中表达显著水平α - IIb - β 3的小鼠出血时间有所改善。静脉注射免疫球蛋白有效地减少了对α IIb β 3产生抗体反应的动物的血小板清除。这些结果表明，以血小板为靶点的基因疗法可以更好地治疗遗传性出血性疾病患者。
Integrins mediate the adhesion of cells to each other and to the extracellular matrix during development, immunity, metastasis, thrombosis, and wound healing. Molecular defects in either the alpha- or beta-subunit can disrupt integrin synthesis, assembly, and/or binding to adhesive ligands. This is exemplified by the bleeding disorder, Glanzmann thrombasthenia (GT), where abnormalities of the platelet-specific integrin, alpha IIb beta 3, prevent platelet aggregation following vascular injury. We previously used a retrovirus vector containing a cDNA cassette encoding human integrin beta 3 to restore integrin alpha IIb beta 3 on the surface of megakaryocytes derived from peripheral blood stem cells of GT patients. In the present study, bone marrow from beta 3-deficient (beta 3(-/-)) mice was transduced with the ITG beta 3-cassette to investigate whether the platelet progeny could establish hemostasis in vivo. A lentivirus transfer vector equipped with the human ITGA2B gene promoter confined transgene expression to the platelet lineage. Human beta 3 formed a stable complex with murine alpha IIb, effectively restoring platelet function. Mice expressing significant levels of alpha IIb beta 3 on circulating platelets exhibited improved bleeding times. Intravenous immunoglobulin effectively diminished platelet clearance in animals that developed an antibody response to alpha IIb beta 3. These results indicate the feasibility of targeting platelets with genetic therapies for better management of patients with inherited bleeding disorders.