Dewey Ricardo A, Avedillo Díez Inés, Ballmaier Matthias, Filipovich Alexandra, Greil Johann, Güngör Tayfun, Happel Christoph, Maschan Alexey, Noyan Fatih, Pannicke Ulrich, Schwarz Klaus, Snapper Scott, Welte Karl, Klein Christoph
Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
Exp Hematol. 2006 Sep;34(9):1161-9. doi: 10.1016/j.exphem.2006.04.021.
Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disorder characterized by recurrent infections, autoimmunity, microthrombocytopenia, and susceptibility to malignant tumors. Compared with the conventional treatment using allogeneic bone marrow transplantation, hematopoietic stem cell gene therapy might offer more specific and less toxic therapeutic options.
We investigated retroviral WAS protein (WASP) gene transfer to assess functional correction and potential toxicities in human CD34(+) cells from WAS patients and healthy individuals, respectively.
WASP mRNA and protein levels were restored in CD14(+) cells derived from WASP-transduced hematopoietic stem cells. Functional reconstitution in WASP-transduced myeloid cells was documented by podosome formation and Fc gamma R-mediated phagocytosis. Importantly, overexpression of WASP in CD34(+) cells from healthy donors did not cause any discernible toxic effects.
Our studies document the feasibility of WASP gene transfer into human CD34(+) cells and suggest that the phenotype of WASP-deficient myeloid cells can be restored upon retroviral gene transfer.
威斯科特-奥尔德里奇综合征（WAS）是一种原发性免疫缺陷疾病，其特征为反复感染、自身免疫、微血小板减少以及易患恶性肿瘤。与使用异基因骨髓移植的传统治疗方法相比，造血干细胞基因治疗可能提供更具特异性且毒性更小的治疗选择。
我们分别研究了逆转录病毒介导的WAS蛋白（WASP）基因转移，以评估其对WAS患者和健康个体的人CD34(+)细胞的功能校正及潜在毒性。
在源自经WASP转导的造血干细胞的CD14(+)细胞中，WASP mRNA和蛋白水平得以恢复。通过足体形成和FcγR介导的吞噬作用证明了经WASP转导的髓样细胞的功能重建。重要的是，健康供体的CD34(+)细胞中WASP的过表达未引起任何可察觉的毒性作用。
我们的研究证明了将WASP基因转移到人CD34(+)细胞中的可行性，并表明逆转录病毒基因转移后，WASP缺陷型髓样细胞的表型可以恢复。
