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
基本信息
- 批准号:8161122
- 负责人:
- 金额:$ 65.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:2&apos-fluoro-5-methylarabinosyluracilAcademiaAcquired Immunodeficiency SyndromeAddressAnimal ModelAnimalsAreaBasic ScienceBiodistributionBiopsyBiopsy SpecimenCancer PatientCardiovascular systemCell Culture TechniquesCell TherapyCell TransplantsCellsCellular ImmunityCellular biologyClinicalColorectal CancerCommunicable DiseasesCommunitiesComplementComplexDevelopmentDiseaseDrug KineticsEndocrineEngineeringEvaluationGene DeliveryGene ExpressionGenesGoalsGrantHematopoietic Stem Cell TransplantationHome environmentHumanImageImaging technologyImmune responseImmunityImmunotherapyIn VitroIndustryInsulin-Dependent Diabetes MellitusIntegraseInvestigational DrugsInvestigational New Drug ApplicationIslet CellLaboratoriesLeadLifeLos AngelesMalignant NeoplasmsMarketingMedicalMedicineMetastatic Neoplasm to the LiverModelingMonitorMusMyocardial dysfunctionNeurologicNew Drug ApprovalsOrganismOutcomeParkinson DiseasePatientsPhasePhysiciansPositron-Emission TomographyProbabilityProceduresProteinsPublic HealthRadiochemistryRegenerative MedicineReporterReporter GenesResearchResearch PersonnelRiskSampling ErrorsSan FranciscoSensitivity and SpecificitySignal TransductionSolutionsStagingStem cellsSystemT-LymphocyteTK2 geneTechnologyTestingTherapeuticTimeTissuesVariantViral ProteinsWorkbasecancer therapycancer typeclinical applicationdesigndosimetryfollow-upgene therapygenetically modified cellshealthy volunteerhuman TK2 proteinimmunogenicimmunogenicityimprovedin vivoindustry partnermelanomamolecular imagingmutantnerve stem cellnoveloncologypre-clinicalpreclinical evaluationproduct developmentresearch clinical testingtherapeutic genetoolvector
项目摘要
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.
PUBLIC HEALTH RELEVANCE: One of the great promises of cell-based therapies is that physicians will find a way to isolate and modify patient's stem cells or T lymphocytes so that they can be re-injected into patients to treat their disease. However, a key challenge is to be able to monitor the cells after they have been administered and see if they survive and engraft, whether they home to areas of disease, and whether they are able to reestablish the activity needed to counteract disease. We are developing novel tools to follow the fate and function of transplanted cells, based on a powerful medical camera called the PET scanner. PET imaging, or positron emission tomography, allows doctors to visualize the biology of cells in living organisms, including patients. The development of novel tools and technologies that will ultimately enable the routine use of PET for clinical monitoring of cell-based therapies in oncology and regenerative medicine represents a complex endeavor that exceeds the capabilities of a typical academic group and carries substantial risks for start-up biotech companies. In our opinion, the solution is an integrated approach in which academic and industry partners work together from the inception of the project, on both discovery and product development phases. The scientific yield from this work may lead to improved therapies for cancer, significantly impacting public health.
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。
公共卫生相关性:基于细胞的疗法的巨大承诺之一是,医生将找到一种分离和修改患者干细胞或T淋巴细胞的方法,以便可以将其重新注入患者以治疗其疾病。但是,一个关键的挑战是能够在细胞被施用后监测它们,看看它们是否生存和植入,是否源于疾病区域,以及它们是否能够重新建立抵消疾病所需的活动。我们正在开发新的工具,以遵循移植细胞的命运和功能,该工具基于一个称为PET扫描仪的强大医疗相机。宠物成像或正电子发射断层扫描使医生可以可视化在内的生物体中(包括患者)细胞的生物学。新型工具和技术的开发最终将使PET常规使用在肿瘤学和再生医学中对基于细胞的疗法进行临床监测,这代表了一项复杂的努力,超过了典型学术组的能力,并具有启动生物技术公司的实质性风险。我们认为,该解决方案是一种综合方法,在该方法中,学术和行业合作伙伴从项目开始,在发现和产品开发阶段都可以共同努力。这项工作的科学产量可能会改善癌症的疗法,从而显着影响公共卫生。
项目成果
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JOHANNES CZERNIN其他文献
JOHANNES CZERNIN的其他文献
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