Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands.
Expert Opin Ther Targets. 2011 Aug;15(8):1003-21. doi: 10.1517/14728222.2011.585971. Epub 2011 Jun 2.
X-linked agammaglobulinemia (XLA) is the most common primary immunodeficiency in man, and is caused by a single genetic defect. Inactivating mutations in the Bruton's tyrosine kinase (BTK) gene are invariably the cause of XLA,. XLA is characterized by a differentiation arrest at the pre-B cell stage, the absence of immunoglobulins and recurrent bacterial infections, making it an insidious disease that gradually disables the patient, and can result in death due to chronic lung disease. Current treatment involves prophylactic antibiotics and immunoglobulin infusions, which are non-curative. This disease is a good candidate for curative hematopoietic stem cell (HSC)-based gene therapy, which could correct the B cell and myeloid deficiencies.
This paper reviews the basic biology of BTK in B cell development, the clinical features of XLA, and the possibilities of gene therapy for XLA, covering the literature from 1995 to 2010.
Work from various laboratories demonstrates the feasibility of using gene-corrected HSCs to complement the immune defects of Btk-deficiency in mice. We propose that it is timely to start clinical programs to develop stem cell based therapy for XLA, using gene-corrected autologous HSC.
X 连锁无丙种球蛋白血症（XLA）是人类最常见的原发性免疫缺陷病，由单一基因缺陷引起。Bruton 酪氨酸激酶（BTK）基因失活突变是 XLA 的必然原因。XLA 的特征是在前 B 细胞阶段分化停滞，缺乏免疫球蛋白和反复细菌感染，使患者逐渐致残，并可能因慢性肺部疾病而死亡。目前的治疗方法包括预防性抗生素和免疫球蛋白输注，但不能治愈。这种疾病是一种很好的基于造血干细胞（HSC）的治愈性基因治疗的候选疾病，可以纠正 B 细胞和髓样细胞缺陷。
本文综述了 BTK 在 B 细胞发育中的基本生物学、XLA 的临床特征以及 XLA 基因治疗的可能性，涵盖了 1995 年至 2010 年的文献。
来自不同实验室的工作表明，使用基因修正的 HSC 来纠正 Btk 缺陷小鼠的免疫缺陷是可行的。我们建议，现在是时候启动临床项目，使用基因修正的自体 HSC 为 XLA 开发基于干细胞的治疗方法了。
