Lentiviral Vector Gene Therapy for CD45 Deliver

CD45 慢病毒载体基因治疗

• 批准号: 6645847
• 负责人: Sybille L Sauter
• 金额: $ 37.44万
• 依托单位: VIROGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6645847
• 关键词: CD antigens; Lentivirus; biotechnology; gene delivery system; gene targeting; gene therapy; hematopoietic stem cells; laboratory mouse; leukocyte activation /transformation; protein tyrosine phosphatase; severe combined immunodeficiency; technology /technique development; transfection /expression vector

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.

描述（由申请人提供）：该项目的总体目标是满足因 CD45 功能丧失而患有严重联合免疫缺陷的患者对有效治疗的需求。 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 功能作用的了解的进展以及 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。 人类和基因敲除小鼠品系中的 CD45 缺陷会导致 T 细胞发育受损以及 T 和 B 细胞功能缺陷。 T 细胞发育缺陷导致外周 T 细胞水平较低，但 B 细胞数量正常甚至增加。 抗原对 B 细胞和 T 细胞的激活严重减弱。 迄今为止报道的两例 CD45 缺乏症病例中，尽管目前有可用的治疗方法，两名患者均在两个月大时就诊，并在两年内死亡。 因此，需要改进该疾病的治疗方法。 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。 具体目标是利用 CD45 小基因的开发来设计，该基因模仿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 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。