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: 8544182
• 负责人: JOHANNES CZERNIN
• 金额: $ 54.62万
• 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/8544182
• 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）：新的分子成像方法来监测基因和基于细胞的疗法基因和基于细胞的疗法，已经迎来了再生医学和肿瘤学的新时代。但是，在有效开发和评估细胞治疗剂时，关键的障碍是无法遵循治疗患者中治疗基因和细胞的命运和功能。我们建议使用正电子发射断层扫描（PET）开发用于特定鉴定和体内治疗基因和细胞的技术，这是一种适用于临床前和临床环境的定量，非侵入性分子成像方法。该应用程序解决了当前报告基因策略的关键局限性，在该策略上，在该策略上修改了治疗载体和细胞，以产生PET可检测的信号。我们将基于完全人类蛋白质生成新颖的宠物报道基因，而不是常用的高度免疫原性病毒蛋白，以克服对临床实施的这一挑战。该项目依靠多年的赠款和基础研究结果，这些结果现在准备晋升为商业领域。我们提出了三年的努力，将最近的进步转变为可作为最终用户准备就绪的宠物记者基因（PRG）输送套件和宠物记者探针（PRP）提供的实践结果，这将使整个身体药代动力学和治疗成果能够提供信息。该应用程序还将提供新的宠物报道探针生物分布和剂量法的第一个人类第0期小试验中的初步信息。我们的建议利用了UCLA（艾哈迈森转化成像部的实验室和哈维·赫斯曼实验室的实验室）与Cellveight Technologies（CST，位于加利福尼亚州旧金山的生物技术公司）之间建立了合作伙伴关系。 UCLA-CST合作伙伴关系建立在UCLA在调查人员和顾问之间的过去广泛互动的基础上，如本申请中所述。我们将执行四个具体目标。 AIM 1由体外，细胞培养和动物研究组成，以评估和优化新的宠物报告基因基因 - PET报告基因探针（PRG-PRP）系统。我们开发的新电流PRG是人胸苷激酶2（TK2）基因的点突变体（N44D）。 L- [18F] FMAU和L- [18F] Feau，两个HTK2-N44D底物是我们的新PRP。在AIM 1中，我们还将确定基于TK2的PRG是否可以引起人类的免疫反应，我们提出了消除这种可能性的策略。在AIM 2中，我们提出了针对两种癌症的基因和基于细胞的疗法的动物模型对新的PRG-PRP系统进行严格的临床前评估：结直肠癌和黑色素瘤的肝转移。 AIM 3提出了一项策略，以开发，验证和商业化PRG将套件交付到鼠和人类治疗细胞中，并计划将这种新能力传播给更广泛的最终用户社区。在AIM 4中，我们将完成一项启发式提交，以实现对新宠物记者探针L-Fmau和L-Feau的生物分布和剂量测定的第一研究。这些“人类第一”研究将为后续研究奠定了基础，在该研究中，UCLA和CST将向FDA提交完整的IND应用，以启动癌症患者新PRG-PRP系统的临床测试。 UCLA和CST研究人员共同开发的一系列新的PET成像技术可能会在癌症的实验基因和基于细胞的基于细胞的疗法中立即发现临床应用，并且可能广泛地适用于具有重大公共健康影响的疾病的疗法，包括对造血细胞的疾病，包括在疾病中，包括先天性疾病中的血液中的疾病中的疾病中的疾病，例如，在诸如先生性和艾滋病中，类型1-疾病中的疾病，类型1-帕金森氏病和心肌功能障碍的干细胞。

项目成果

High-pressure, compact, modular radiosynthesizer for production of positron emitting biomarkers.

高压、紧凑、模块化放射合成仪，用于生产正电子发射生物标记物。

• DOI: 10.1016/j.apradiso.2013.04.024
• 发表时间: 2013
• 期刊: Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine
• 作者: Amaraesekera,Bernard;Marchis,PhillipD;Bobinski,KrzysztofP;Radu,CaiusG;Czernin,Johannes;Barrio,JorgeR;MichaelvanDam,R
• 通讯作者: MichaelvanDam,R