Lentiviral Vector Gene Therapy for CD45 Deliver

描述（由申请人提供）：该项目的总体目标是解决由于CD45功能丧失而导致的严重联合免疫缺陷患者的有效治疗需求。CD45缺乏症是导致严重联合免疫缺陷（SCID）的一组遗传性疾病之一。对CD45功能作用的认识的进步和CD45敲除小鼠表型特性的证明，为在相当大比例的具有未知遗传缺陷的SCID患者中寻找CD45畸变提供了理论依据。人和敲除小鼠品系的CD45缺失导致T细胞发育受损和T细胞和B细胞功能缺陷。T细胞发育缺陷产生低水平的外周T细胞，但B细胞数量正常甚至增加。B细胞和T细胞被抗原激活严重减弱。在目前已报道的两例CD45缺乏症中，尽管目前有可用的治疗方法，但这两例患者均在两个月大时出现并在两年内死亡。因此，有必要改进这种疾病的治疗方法。我们建议开发一种cd45替代基因疗法来纠正患者造血细胞的遗传缺陷，从而提供更好的治疗。特异性目标是利用CD45基因的发展来模拟造血表达特征和天然基因的谱系特异性表达模式，并恢复CD45缺失细胞的免疫功能。重要的是，该项目利用了我们在慢病毒基因转移载体技术方面的丰富经验。

DESCRIPTION (provided by the applicant): The overall goal of this project is to address the need for an effective therapy for patients with severe combined immunodeficiency due to loss of CD45 function. CD45 deficiency is one of a group of genetic diseases that results in severe combined immunodeficiency (SCID). Advances in knowledge of the role of CD45 function and the demonstration of the phenotypic properties of CD45 knockout mice provided the rationale to look for CD45 aberrations in the fairly large proportion of SCID patients with unknown genetic defects. CD45 deficiency in man and knockout mouse strains results in impaired T cell development and defective T and B cell functional capabilities. The T cell developmental defects produce low levels of peripheral T cells but normal or even increased B cell numbers. Activation of B and T cells by antigen is severely diminished. In the two cases of CD45 deficiency that have been reported thus far, both patients presented at two months of age and died within two years in spite of currently available therapies. Thus, there is a need for improved therapies for this disease. We propose to develop a CD45-replacement gene therapy to correct the genetic deficiency in the patients' hematopoietic cells and thereby provide a superior treatment. The specific aims are designed the take advantage of the development of a CD45 minigene which mimics the hematopoietic expression characteristics and lineage specific expression patterns of the native gene and which also, restores immune function to CD45-null cells. Importantly, the project utilizes our considerable experience with lentiviral gene transfer vector technology.