Role of co-receptor modified cells in HIV infection

共受体修饰细胞在 HIV 感染中的作用

• 批准号: 8469110
• 负责人: CARL H. JUNE
• 金额: $ 128.7万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469110
• 关键词: AIDS/HIV problem; Adenovirus Vector; Adenoviruses; Alleles; Allogenic; Antiviral Agents; Autoimmune Diseases; Autologous; Berlin; Binding; Blood; CCR; CCR5 gene; CD4 Positive T Lymphocytes; Cancer Patient; Cell Therapy; Cells; Cleaved cell; Clinical Trials; Cyclophosphamide; Data; Disease; Dose; Engineering; Engraftment; Future; Generations; Genes; Globulins; Goals; HIV; HIV Infections; HIV-1; Highly Active Antiretroviral Therapy; Human; Immunotherapy; Infusion procedures; Interruption; Lymphopenia; Messenger RNA; Outcome; Patients; Phase; Play; Procedures; Proteins; Protocols documentation; RNA; Resistance; Role; Safety; Structure; T-Lymphocyte; Testing; Therapeutic immunosuppression; Tissues; Zinc Fingers; base; chemotherapy; conditioning; cost; design; experience; gene therapy; human data; improved; insight; mRNA Expression; novel strategies; nuclease; phase 1 study; receptor; research clinical testing; research study; response

The central hypothesis of this Project 1 is that CCR5-deficient, C04-)- T-cells played a major role in contributing to the successful outcome of the Berlin patient. Our approach is tiased on our expertise with cell'based therapies for HIV infection as well as the first in-human data from Infusions of autologous CD4 cells rendered CCRS-deficient by zinc finger nucleases (ZFNs), whk:h bind to, cleave and Inactivate the ccrS gene. Phase-I data from this trial demonstrated an excellent safety profile as well as efficient, long-temn engraftment and expansion of the CCRS-modified cells. Furthermore, while not a direct goal of this trial, intriguing antiviral effects have been observed in 6 subjects at Penn who completed a 12 week treatment interruption, in this project we will detennine if patient conditioning with a single dose of cyclophosphamide that is used routinely in autoimmune disorders and to promote immunotherapy can enhance engraftment of autologous T-cells treated with RS-spedfic ZFNs, and as a result, control HIV In the absence of H/\/^T. Three specific aims are proposed: (1) Complete the pre-clinical testing necessary to support the manufacturing of mRNA ZFN modified CD4 T cells; (2) Conduct a proof of concept clinical trial to detennine the safety of R5 deficient CD4 cells infused in the setting of transient lymphopenia, induced with a single dose of cyclophosphamide and (3) Evaluate the host and virotogical response to R5-modified T ceil infusions. We hypothesize that the level of engraftment will increase in the cyclophosphamide-treated patients, and related to this, ttiat antiviral effects will be uncovered during a structured treatment interruption. Curing or controlling HIV in the absence of HAART has been an elusive goal, but one that may finally be realized. The results of our project, conducted with an experienced team in place at Sangamo and Penn will provide critical information for future protocols to further dtesect the factors that led to cure of the Beriin patient and provide basic insights into underiying mechanisms.

该项目1的中心假设是CCR5缺陷，C04-） - T细胞在 促进柏林患者的成功结果。我们的方法是我们的​​专业知识 基于细胞的HIV感染疗法以及自体CD4输注的第一个人类数据 细胞通过锌指核酸酶（ZFN），WHK：H结合，裂解和失活CCR，使CCR缺乏CCR。 基因。该试验的I阶段数据表明了出色的安全性以及高效，长期的 CCRS修饰细胞的植入和扩展。此外，虽然不是这次审判的直接目标，但 在完成12周治疗的宾夕法尼亚州的6名受试者中，已经观察到了有趣的抗病毒作用 中断，在这个项目中，如果患者用单剂量的环磷酰胺进行调节，我们将发酵 通常用于自身免疫性疾病并促进免疫疗法可以增强植入 用RS-Spedfic ZFN处理的自体T细胞，因此，在没有H/\/^T的情况下控制HIV。 提出了三个具体目的：（1）完成支持该临床前测试 mRNA ZFN修饰的CD4 T细胞的生产； （2）对Detennine进行概念临床试验证明 R5缺乏CD4细胞在瞬时淋巴细胞减少症中注入 环磷酰胺的剂量和（3）评估宿主和对R5修饰T CEIL的宿主和病毒反应 输注。我们假设植入水平将在经环磷酰胺治疗的 患者以及与此相关的，在结构化治疗中断期间将发现Tttiat抗病毒药作用。 在没有HAART的情况下治愈或控制艾滋病毒一直是一个难以捉摸的目标，但最终可能是 实现。我们项目的结果与在Sangamo和Penn的经验丰富的团队一起进行 为未来的协议提供关键信息，以进一步探讨导致Beriin治愈的因素 患者并提供有关不足机制的基本见解。