Lentiviral Vector Gene Therapy for CD45 Deliver

CD45 慢病毒载体基因治疗

• 批准号: 6751633
• 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 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6751633
• 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解决由于CD45功能丧失而导致严重合并免疫缺陷患者进行有效治疗的需求。 CD45缺乏是导致严重合并免疫缺陷（SCID）的一组遗传疾病之一。 了解CD45功能的作用的知识以及CD45敲除小鼠的表型特性的证明提供了基本原理，以在相当大的遗传缺陷的SCID患者中寻找CD45畸变。 CD45人体和基因敲除小鼠菌株的缺乏会导致T细胞发育受损以及T和B细胞功能能力有缺陷。 T细胞发育缺陷会产生低水平的外围T细胞，但B细胞数正常甚至增加。 通过抗原激活B和T细胞的激活严重减少。 迄今为止，在两种CD45缺乏症的情况下，两名患者都在两个月大时出现，尽管目前可用的疗法都在两年内死亡。 因此，需要改善该疾病的疗法。 我们建议开发一种CD45替代基因治疗，以纠正患者造血细胞的遗传缺乏，从而提供出色的治疗。 设计的目的是利用CD45小型基因的开发，该CD45微基模拟了天然基因的造血表达特征和谱系特定表达模式，并还可以恢复对CD45-NULL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媒介技术方面的丰富经验。