HIV-1 vector mediated gene therapy for HIV-1 infection

描述（由申请人提供）：艾滋病毒感染全球4000万人。在美国，据估计，大约有100万人感染了艾滋病毒。据估计，全世界每年因HIV/AIDS导致的死亡率约为300万，其中美国每年有15，000人死亡。目前治疗HIV的护理标准是HAART，或高效抗逆转录病毒疗法。然而，HAART非常昂贵，并且需要繁琐的给药方案。更重要的是，由于药物治疗，越来越多的耐药HIV毒株正在出现，这些耐药毒株正在传播给新感染的个体。这一艾滋病毒耐药患者亚群没有其他治疗方法，因此预后非常差。我们的总体目标是证明基于HIV-1的载体在延迟或预防艾滋病（HIV引起的疾病）发作方面的安全性和有效性。我们的技术使用HIV作为骨架，将抗HIV基因传递给受感染的CD 4 T细胞，这些细胞是HIV复制的靶细胞。我们已经在I期SBIR资金支持的研究中证明，携带抗HIV反义遗传有效载荷（VRX 496）的HIV载体有效抑制患者CD 4 T细胞中的生产性HIV复制，而不依赖于患者病毒载量、CD 4计数和病毒嗜性。该资助中拟议研究的关键技术目标是表征我们疗法的风险/效益比，并开发和验证内部大规模患者细胞处理技术，为美国疗效临床试验做准备。为此，我们的具体目标是：1）确定慢病毒基因转移是否在体内诱导克隆性T细胞淋巴增殖，并在健康和HIV感染的成人和儿童供体中目录插入位点，2）通过纵向测量VRX 496治疗的患者中的免疫应答来评估我们的疗法在免疫重建方面的功效，以及3）开发和验证用于HIV基因疗法治疗的内部大规模细胞处理技术。这三个关键目标与产品的整体安全性和有效性密切相关，这是向那些没有其他治疗选择的患者提供我们的治疗的重要一步。

DESCRIPTION (provided by applicant): HIV infects 40 million people worldwide. In the United States (U.S.), it is estimated that almost one million people are infected with HIV. The mortality due to HIV/AIDS is estimated to be approximately three (3) million deaths annually worldwide, with 15,000 deaths per year in the U.S. The current standard of care for treatment of HIV is HAART, or highly active antiretroviral therapy. However, HAART is very expensive and requires a cumbersome dosing regimen. More importantly, an increasing number of resistant HIV strains are emerging as a result of drug therapy, and these resistant strains are being transmitted to newly infected individuals. This subpopulation of HIV drug-resistant patients has no treatment alternatives and therefore has a very poor prognosis. Our overall goal is to demonstrate the safety and efficacy of HIV-1-based vectors in delaying or preventing the onset of AIDS, the disease caused by HIV. Our technology uses HIV as a backbone to deliver an anti-HIV gene to infected CD4 T cells, which are the target cells for HIV replication. We have demonstrated in studies supported by Phase I SBIR funding that an HIV vector carrying an anti- HIV antisense genetic payload (VRX496) effectively inhibits productive HIV replication in patient CD4 T cells independent of patient viral load, CD4 count, and virus tropism. The key technological objectives of the proposed studies in this grant are to characterize the risk/benefit ratio of our therapy, and develop and validate the technology in-house for large-scale patient cell processing in preparation for U.S. efficacy clinical trials. To this end, our specific aims are: 1) determine whether lentiviral gene transfer induces clonal T cell lymphoproliferation in vivo, and catalog insertion sites in healthy and HIV-infected adult and pediatric donors, 2) evaluate the efficacy of our therapy in terms of immune reconstitution by measuring the immunological responses in VRX496-treated patients longitudinally, and 3) develop and validate the technology for in house large-scale cell processing for gene therapy treatment of HIV. These three key objectives are closely associated with the overall product safety and efficacy, which is an important step in moving forward to making our therapy available to those patients who would otherwise have no alternative treatment options.