STEM CELL GENE THERAPY FOR AIDS USING AN ANTI-SIV ENVELOPE ANTISENSE MOLECULE

使用抗 SIV 包膜反义分子治疗艾滋病的干细胞基因疗法

• 批准号: 7715502
• 负责人: Stephen Edward Braun
• 金额: $ 12.98万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-05 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715502
• 关键词: Acquired Immunodeficiency Syndrome; CD34 gene; CD4 Positive T Lymphocytes; Cell Line; Cells; Computer Retrieval of Information on Scientific Projects Database; Coupled; Exhibits; Funding; Genes; Grant; HIV; HIV-1; Hematopoietic stem cells; Immune; Immunologic Deficiency Syndromes; In Vitro; Infection; Institution; Lentivirus Vector; Life; Light; Lymphoid; Macaca; Macaca mulatta; Mediating; Modeling; Preclinical Testing; Proteins; Range; Research; Research Personnel; Resistance; Resources; SIV; Source; Stem Cell Development; Stem cells; T-Lymphocyte; United States National Institutes of Health; Viral; base; gene therapy; progenitor; reconstitution; transduction efficiency; vector

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The introduction of inhibitory genes into hematopoietic stem cells offers the potential for long-lived immune reconstitution with progeny cells resistant to HIV-1 replication. However, successful development of stem cell gene therapy for AIDS is likely to require preclinical testing in the rhesus macaque model. In light of recent findings demonstrating that the rhesus macaque TRIM5alpha protein inhibits infection of macaque cells by HIV-1, simian immunodeficiency (SIV)-based lentiviral vectors may have distinct advantages over HIV-1-based vectors for the transduction of macaque hematopoietic stem cells. We evaluated the ability of a SIV-based lentiviral vector (VRX859) to inhibit viral replication in vitro and to transduce rhesus CD34+ lymphoid progenitor cells. Following infection with homologous SIV strains, CD4+ cell lines transduced with the VRX859 vector exhibited over 600-fold inhibition of viral replication compared to control cells. Less inhibition was observed with the divergent SIV strain SIVsmE660. Transduction of rhesus CD34+ cells with VRX859 over a range of MOIs resulted in comparable transduction efficiency as observed with the HIV vector VRX494. However, when we evaluated transduction of rhesus T lymphocyte progenitors, we observed more efficient transduction with the SIV-based vector. CD4+ T cells derived from VRX859-transduced CD34+ cells strongly inhibited SIVmac239 replication as compared to control CD4+ T cells. The ability of this SIV-based vector to mediate potent inhibition of SIV replication, coupled with its efficient transduction of rhesus hematopoietic progenitor cells, make it an attractive candidate for trials of stem cell gene therapy in the SIV/macaque model.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 将抑制基因引入造血干细胞，为子代细胞抵抗 HIV-1 复制提供了长期免疫重建的潜力。 然而，成功开发艾滋病干细胞基因疗法可能需要在恒河猴模型中进行临床前测试。 鉴于最近的研究结果表明恒河猴 TRIM5alpha 蛋白可抑制 HIV-1 对猕猴细胞的感染，基于猿猴免疫缺陷 (SIV) 的慢病毒载体在转导猕猴造血干细胞方面可能比基于 HIV-1 的载体具有明显的优势。 我们评估了基于 SIV 的慢病毒载体 (VRX859) 在体外抑制病毒复制和转导恒河猴 CD34+ 淋巴祖细胞的能力。在用同源 SIV 毒株感染后，用 VRX859 载体转导的 CD4+ 细胞系与对照细胞相比，表现出超过 600 倍的病毒复制抑制。 在不同的 SIV 毒株 SIVsmE660 中观察到较少的抑制。使用 VRX859 在一定 MOI 范围内转导恒河猴 CD34+ 细胞，其转导效率与使用 HIV 载体 VRX494 观察到的转导效率相当。 然而，当我们评估恒河猴 T 淋巴细胞祖细胞的转导时，我们观察到基于 SIV 的载体的转导效率更高。 与对照 CD4+ T 细胞相比，源自 VRX859 转导的 CD34+ 细胞的 CD4+ T 细胞强烈抑制 SIVmac239 复制。 这种基于 SIV 的载体能够有效抑制 SIV 复制，加上其对恒河猴造血祖细胞的有效转导，使其成为 SIV/猕猴模型中干细胞基因治疗试验的有吸引力的候选者。