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: 8889623
• 负责人: CARL H. JUNE
• 金额: $ 156.67万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8889623
• 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 缺陷的 C04-)- T 细胞在 为柏林患者的成功治疗做出了贡献。我们的方法是基于我们的专业知识 HIV 感染的细胞疗法以及自体 CD4 输注的首个人体数据 锌指核酸酶 (ZFN) 导致 CCRS 缺陷的细胞，whk:h 结合、裂解和灭活 ccrS 基因。该试验的第一阶段数据展示了出色的安全性以及高效、长期的效果。 CCRS 修饰细胞的植入和扩增。此外，虽然不是本次试验的直接目标， 在宾夕法尼亚大学完成 12 周治疗的 6 名受试者中观察到了有趣的抗病毒效果 中断，在这个项目中，我们将确定是否使用单剂量环磷酰胺调节患者 常规用于自身免疫性疾病并促进免疫治疗，可以增强 用 RS 特异性 ZFN 处理自体 T 细胞，结果在没有 H/\/^T 的情况下控制了 HIV。 提出了三个具体目标：（1）完成必要的临床前测试以支持 mRNA ZFN 修饰的 CD4 T 细胞的制造； (2) 进行概念验证临床试验以确定 在短暂性淋巴细胞减少症的情况下输注 R5 缺陷型 CD4 细胞的安全性，由单一 环磷酰胺的剂量和（3）评估宿主和病毒学对 R5 修饰 T 细胞的反应 输液。我们假设经过环磷酰胺处理的植入水平会增加 患者，与此相关的是，在结构化治疗中断期间将发现抗病毒作用。 在没有 HAART 的情况下治愈或控制 HIV 一直是一个难以捉摸的目标，但最终可能会实现 意识到了。我们的项目由桑加莫和宾夕法尼亚大学经验丰富的团队进行，其结果将 为未来的方案提供关键信息，以进一步检测导致贝里因治愈的因素 耐心并提供对潜在机制的基本见解。