Novel molecular imaging approaches to monitor gene and cell-based therapies

监测基因和细胞疗法的新型分子成像方法

• 批准号: 8324201
• 负责人: JOHANNES CZERNIN
• 金额: $ 59.31万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8324201
• 关键词: 2' -fluoro-5-methylarabinosyluracil; Academia; Acquired Immunodeficiency Syndrome; Address; Animal Model; Animals; Area; Basic Science; Biodistribution; Biopsy; Biopsy Specimen; Cancer Patient; Cardiovascular system; Cell Culture Techniques; Cell Therapy; Cell Transplants; Cells; Cellular Immunity; Cellular biology; Clinical; Colorectal Cancer; Communicable Diseases; Communities; Complement; Complex; Development; Disease; Drug Kinetics; Endocrine; Engineering; Evaluation; Gene Delivery; Gene Expression; Genes; Goals; Grant; Hematopoietic Stem Cell Transplantation; Home environment; Human; Image; Imaging technology; Immune response; Immunity; Immunotherapy; In Vitro; Industry; Insulin-Dependent Diabetes Mellitus; Integrase; Investigational Drugs; Investigational New Drug Application; Islet Cell; Laboratories; Lead; Life; Los Angeles; Malignant Neoplasms; Marketing; Medical; Medicine; Metastatic Neoplasm to the Liver; Modeling; Monitor; Mus; Myocardial dysfunction; Neurologic; New Drug Approvals; Organism; Outcome; Parkinson Disease; Patients; Phase; Physicians; Positron-Emission Tomography; Probability; Procedures; Proteins; Public Health; Radiochemistry; Regenerative Medicine; Reporter; Reporter Genes; Research; Research Personnel; Risk; Sampling Errors; San Francisco; Sensitivity and Specificity; Signal Transduction; Solutions; Staging; Stem cells; System; T-Lymphocyte; TK2 gene; Technology; Testing; Therapeutic; Time; Tissues; Variant; Viral Proteins; Work; base; cancer therapy; cancer type; clinical application; design; dosimetry; follow-up; gene therapy; genetically modified cells; healthy volunteer; human TK2 protein; immunogenic; immunogenicity; improved; in vivo; industry partner; melanoma; molecular imaging; mutant; nerve stem cell; novel; oncology; pre-clinical; preclinical evaluation; product development; research clinical testing; therapeutic gene; tool; vector

DESCRIPTION (provided by applicant): Novel molecular imaging approaches to monitor gene and cell-based therapies Gene and cell-based therapies have ushered in a new era of opportunities in regenerative medicine and oncology. However, a critical roadblock in the effective development and evaluation of cellular therapeutics is the inability to follow the fate and function of the therapeutic genes and cells in treated patients. We propose to develop technologies for specific identification and tracking of therapeutic genes and cells in vivo using positron emission tomography (PET), a quantitative, non-invasive molecular imaging approach applicable to both preclinical and clinical settings. This application addresses a key limitation of current reporter gene strategies, in which therapeutic vectors and cells are genetically modified to produce a signal detectable by PET. Instead of commonly used, highly immunogenic viral proteins, we will generate novel PET reporter genes based on fully human proteins, to overcome this challenge to clinical implementation. This project relies on many years of grants and basic research results that are now ready to advance to the commercial domain. We propose a three year effort to turn recent advances into practical outcomes delivered as end-user-ready PET Reporter Gene (PRG) delivery kits and PET Reporter Probes (PRP) that will enable whole body pharmacokinetic and therapeutic outcomes information. This application will also deliver preliminary information from a first-in-human Phase 0 small trial of new PET reporter probe biodistribution and dosimetry. Our proposal leverages an established partnership between UCLA (the laboratories of the Ahmanson Translational Imaging Division and the laboratory of Harvey Herschman) and CellSight Technologies (CST, a biotech company based in San Francisco, CA). The UCLA-CST partnership builds on past extensive interactions at UCLA between investigators and consultants, as described in this application. We will carry out four Specific Aims. Aim 1 consists of in vitro, cell culture and animal studies to evaluate and optimize new PET Reporter Gene-PET Reporter Probe (PRG-PRP) systems. Our new current PRG being developed is a point mutant (N44D) of the human thymidine kinase 2 (tk2) gene. L-[18F]FMAU and L- [18F]FEAU, two hTK2-N44D substrates, are our new PRPs. In Aim 1 we will also determine whether the TK2- based PRG can elicit an immune response in humans and we propose a strategy to eliminate this possibility. In Aim 2 we propose a stringent preclinical evaluation of the new PRG-PRP systems, using animal models of gene and cell-based therapies against two types of cancer: hepatic metastases of colorectal cancer and melanoma. Aim 3 proposes a strategy to develop, validate, and commercialize kits for PRG delivery into murine and human therapeutic cells and a plan to disseminate this new capability to wider communities of end- users. In Aim 4 we will complete an eIND submission to enable first-in-human studies of the biodistribution and dosimetry of the new PET reporter probes L-FMAU and L-FEAU. These "first-in-human" studies will set the stage for a follow-up study in which UCLA and CST will submit a full IND application to the FDA to initiate clinical testing of the new PRG-PRP systems in cancer patients. The set of new PET imaging technologies co-developed by UCLA and CST investigators may find immediate clinical applications in experimental gene and cell-based therapies in cancer and may be broadly applicable to therapies for diseases with significant public health impact, including transplantation of hematopoietic stem cells in congenital and acquired disorders such as AIDS, islet cells in type 1 diabetes, ES-derived neural stem cells in Parkinson's disease, and stem cells in myocardial dysfunction.

描述（由申请人提供）：用于监测基于基因和细胞的治疗的新型分子成像方法基因和基于细胞的治疗已经迎来了再生医学和肿瘤学的新时代。然而，有效开发和评估细胞疗法的一个关键障碍是无法跟踪治疗患者中治疗基因和细胞的命运和功能。我们建议开发的技术，具体识别和跟踪治疗基因和细胞在体内使用正电子发射断层扫描（PET），定量，非侵入性的分子成像方法，适用于临床前和临床设置。本申请解决了当前报告基因策略的关键限制，其中治疗载体和细胞被遗传修饰以产生可通过PET检测的信号。我们将基于全人类蛋白质生成新型PET报告基因，而不是常用的高免疫原性病毒蛋白质，以克服临床实施的这一挑战。该项目依赖于多年的赠款和基础研究成果，现在已经准备好进入商业领域。我们提出了一项为期三年的努力，将最近的进展转化为实际成果，作为最终用户准备好的PET报告基因（PRG）交付试剂盒和PET报告探针（PRP），这将使全身药代动力学和治疗结果信息。该应用程序还将提供新PET报告探针生物分布和剂量测定的首次人体0期小型试验的初步信息。我们的提案利用了加州大学洛杉矶分校（Ahmanson翻译成像部门的实验室和Harvey Herschman的实验室）和CellSight Technologies（CST，一家位于加利福尼亚州旧金山弗朗西斯科的生物技术公司）之间建立的合作伙伴关系。加州大学洛杉矶分校-科技委的伙伴关系建立在加州大学洛杉矶分校研究人员和顾问之间过去广泛的互动，如本申请所述。我们将实现四个具体目标。目的1通过体外、细胞培养和动物实验，对新型PET报告基因-PET报告探针（PRG-PRP）系统进行评价和优化。我们目前正在开发的新PRG是人胸苷激酶2（tk 2）基因的点突变体（N44 D）。L-[18F]FMAU和L- [18F]FEAU是两种hTK 2-N44 D底物。在目标1中，我们还将确定基于TK 2的PRG是否可以在人体中引发免疫应答，并提出了消除这种可能性的策略。在目标2中，我们提出了一个严格的临床前评估的新PRG-PRP系统，使用动物模型的基因和细胞为基础的治疗对两种类型的癌症：肝转移的结直肠癌和黑色素瘤。目标3提出了一项战略，以开发，验证和商业化的试剂盒PRG交付到鼠和人的治疗细胞和计划，传播这种新的能力，以更广泛的社区的最终用户。在目标4中，我们将完成eIND提交，以实现新型PET报告探针L-FMAU和L-FEAU的生物分布和剂量测定的首次人体研究。这些“首次人体”研究将为后续研究奠定基础，其中加州大学洛杉矶分校和CST将向FDA提交完整的IND申请，以启动新PRG-PRP系统在癌症患者中的临床试验。由加州大学洛杉矶分校和CST研究人员共同开发的一套新的PET成像技术可能会立即在癌症的实验性基因和细胞治疗中找到临床应用，并可能广泛适用于对公共卫生有重大影响的疾病的治疗，包括移植造血干细胞在先天性和获得性疾病，如艾滋病，胰岛细胞在1型糖尿病，帕金森病中的ES衍生神经干细胞，以及心肌功能障碍中的干细胞。