Lentiviral Vector Gene Therapy for CD45 Deliver

描述（由申请方提供）：本项目的总体目标是解决因CD45功能丧失而导致重度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功能作用的认识和CD45基因敲除小鼠表型特性的证明的进展为在相当大比例的具有未知遗传缺陷的SCID患者中寻找CD45畸变提供了理论基础。 人和敲除小鼠品系中的CD 45缺陷导致T细胞发育受损以及T和B细胞功能能力缺陷。 T细胞发育缺陷产生低水平的外周T细胞，但产生正常或甚至增加的B细胞数量。 抗原对B和T细胞的激活作用严重减弱。 在迄今为止报告的两例CD45缺乏症病例中，尽管目前有可用的治疗方法，但两例患者均在两个月大时就诊，并在两年内死亡。 因此，需要改善这种疾病的治疗。 我们建议开发一种CD 45替代基因疗法，以纠正患者造血细胞中的遗传缺陷，从而提供一种上级治疗。 具体目的是利用CD45小基因的开发，该小基因模拟天然基因的造血表达特征和谱系特异性表达模式，并且还恢复对CD45无效细胞的免疫功能。 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.