Foamy Virus Mediated gene Therapy in the Canine SCID-X1 model

项目2的目标是研究造血干细胞(HSC)基因疗法的有效性和安全性。 FV载体在犬SCID-XL模型中的应用研究项目： 人类患者已经表明，插入突变是SCID治疗中的一个重要问题。 XL+HSC基因治疗。犬SCID-X1模型是一种试验新型的优秀大动物模型 SC1D-X1的基因治疗和移植策略。犬X连锁SCID 综合征，就像人类一样，是由IL-2、IL-4、IL-4的共同伽马亚单位(YC)突变引起的。 7、IL-9和IL-15受体。和人类一样，患有SCID-XL的新生犬外周T细胞很少，而且 外周血B细胞数量增加。犬SCID-XL中的B细胞能够产生IgM，但不能 能够转换为免疫球蛋白抗体。犬SCID-XL模型已被广泛应用于研究 骨髓移植和基因治疗策略。犬类研究的一个主要优势是能够 对疗效和安全性进行长期评估。在这里，我们建议研究新的FV载体和 非清髓性预适应提高SCID-X1基因治疗的有效性和安全性。我们假设 FV载体将在SCID-XL犬中提供更安全的整合位点轮廓，类似于我们在 正常的狗。我们进一步假设，新的非清髓性调节方案将会改善 植入经过基因修正的造血干细胞，从而改善长期免疫重建。此外，我们 验证体内注射FV载体可促进免疫重建的假设。 项目2将与所有其他项目和核心密切互动。具体地说，项目2将与 Rawling博士和Scharenberg博士将在项目1的小鼠模型中评估FV载体。我们还将 与项目3的项目负责人Trobridge博士密切合作，评估新的集成站点分析和 潜在的改进，绝缘的FV载体。我们将利用所有核心。核心A将促进沟通 在不同的项目和核心中，核心B将提供所有FV矢量。核心C将协助研究 评估SCID-XL犬的免疫重建，核心D将协助FV载体整合部位 分析。 相关性： 项目2的目标是研究造血干细胞(HSC)基因疗法的有效性和安全性。 使用泡沫病毒载体的严重联合免疫缺陷(SCID-XL)。拟议的研究引入了 几个可能改变当前研究或临床实践范式的新概念 这种遗传的免疫系统X连锁疾病。

The goal of Project 2 is to study the efficacy and safety of hematopoietic stem cell (HSC) gene therapy for severe combined immunodeficiency (SC1D-X1) using FV vectors in the canine model of SCID-Xl. Studies in human patients have shown that insertional mutagenesis is a substantial concern in the treatment of SCID- Xl with HSC gene therapy. The canine SCID-X1 model is an outstanding large animal model to test novel gene therapy and transplantation strategies for the treatment of SC1D-X1. The canine X-linked SCID syndrome, just as in humans, is caused by mutations in the common gamma subunit (yc) of the IL-2, IL-4, IL- 7, IL-9 and lL-15 receptors. As in humans, neonatal dogs with SCID-Xl have few peripheral T cells, and the number of peripheral B cells is increased. B cells in canine SCID-Xl are able to produce IgM but are not capable of class-switching to IgG antibodies. The canine SCID-Xl model has been extensively used to study bone marrow transplantation and gene therapy strategies. A major strength of canine studies is the ability to perform long-term evaluations of efficacy and safety. Here we propose to study novel FV vectors and nonmyeloablative conditioning to improve efficacy and safety of gene therapy for SCID-X1. We hypothesize that FV vectors will provide a safer integration site profile in SCID-Xl dogs similar to our preliminary data in normal dogs. We further hypothesize that novel nonmyeloablative conditioning regimens will improve engraftment of gene-corrected HSCs and thus improve long-term immune reconstitution. Furthermore, we test the hypothesis that in vivo administration of FV vectors may improve immune reconstitution. Project 2 will interact closely with all other projects and cores. Specifically, Project 2 will closely work with Drs. Rawlings and Scharenberg who will evaluate FV vectors in the mouse model in Project 1. We will also closely work with Dr. Trobridge, Project Leader of Project 3, to evaluate novel integration site analyses and potentially improved, insulated FV vectors. We will utilize all cores. Core A will facilitate communication among the different projects and cores, Core B will provide all FV vectors. Core C will assist with studies to evaluate immune reconstitution in SCID-Xl dogs, and Core D will assist with the FV vector integration site analyses. RELEVANCE: The goal of Project 2 is to study the efficacy and safety of hematopoietic stem cell (HSC) gene therapy for severe combined immunodeficiency (SCID-Xl) using foamy virus vectors. The proposed studies introduce several novel concepts that may change current research or clinical practice paradigms for the treatment of this inherited X-linked disorder of the immune system.