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.

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