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: 7562120
• 负责人: Stephen E. Braun
• 金额: $ 5.21万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7562120
• 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 TRIM5a 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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 将抑制性基因引入造血干细胞中，具有抗HIV-1复制具有抵抗力的后代细胞的长寿命免疫重建的潜力。 然而，成功开发用于艾滋病的干细胞基因治疗可能需要在恒河猴模型中进行临床前测试。 鉴于最近的发现表明，恒河猴Trim5a蛋白抑制了HIV-1的猕猴细胞感染，基于HIV（SIV）的慢病毒载体（SIV）的慢病毒载体可能比基于HIV-1的载体具有明显的优势，用于转导猕猴血肿造血性干细胞。 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。与同源SIV菌株感染后，与对照细胞相比，用VRX859载体转导的CD4+细胞系对病毒复制的抑制作用超过600倍。 用不同的SIV菌株SIVSME660观察到抑制作用较少。如HIV载体VRX494所观察到的，用VRX859在一定范围内用VRX859转导恒河部CD34+细胞导致了可比的转导效率。 但是，当我们评估恒河猴的转导淋巴细胞祖细胞时，我们观察到了基于SIV的载体的有效转导。 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的复制。 该基于SIV的载体介导有效抑制SIV复制的能力，再加上其有效的恒河猴造血祖细胞的转导，使其成为SIV/猕猴模型中干细胞Gene治疗试验的有吸引力的候选者。