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Mechanisms of Caspase-1 Mediated Schwannoma Regression

Caspase-1 介导神经鞘瘤消退的机制

基本信息

批准号：
9125667
负责人：
GARY JAY BRENNER
金额：
$ 36.38万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9125667
关键词：
Animals Apoptosis Apoptotic Benign Biochemical Biological Biological Assay Biology Bystander Effect CASP1 gene Caspase Cause of Death Cell Death Cell Lineage Cells Cessation of life Clinical Code Culture Media DNA Data Dependovirus Development Disease Disease Management Elements Environment Genes Goals Grant Hereditary Disease Human Image Immune Immune response Immunocompetent Implant In Vitro Infection Inflammatory Injection of therapeutic agent Investigation Lead Lesion Location Magnetic Resonance Imaging Manuscripts Mediating Medical Modeling Molecular Monitor Mus Myelin Sheath NF1 gene Natural Killer Cells Neoplasms Nerve Neurilemmoma Neurofibromatoses Neurofibromatosis 2 Neurons Non-Malignant Nude Mice Pathway interactions Patients Peripheral Nerves Peripheral Nervous System Neoplasms Primary Neoplasm Publishing Research Resistance to infection Schwann Cells Schwannomatosis Stream Techniques Testing Therapeutic Therapeutic Effect Time Toxic effect Treatment Efficacy Tumor Volume Tumor-Derived Viral Vector Virus adaptive immunity adeno-associated viral vector cytokine disability exosome gene therapy clinical trial implantation in vivo individual patient innovation killings microvesicles myelination neoplastic cell neurotoxicity novel novel therapeutic intervention novel therapeutics preclinical study promoter protein complex response sciatic nerve treatment strategy tumor tumor growth vector vector control

项目摘要

DESCRIPTION (provided by applicant): While schwannoma tumors are typically benign (non-malignant) they can have devastating consequences for patients. As for an individual patient there is often no efficacious treatment. Thus, schwannoma therapy represents a major unmet clinical need. We have developed a new therapeutic approach to these nerve-associated tumors that involves intra-tumoral injection of an adeno-associated virus (AAV) vector carrying the pro-apoptotic gene caspase-1 (ICE) under a Schwann-cell specific promoter (P0); the vector is denoted AAV-P0-ICE. Our pre-clinical studies have shown a remarkable ability of the AAV-P0- ICE vector to produce a prolonged reduction in tumor volume with no nerve damage (manuscript submitted). Our preliminary data suggests that AAV-PO-ICE not only directly kills infected caspase-1-expressing tumor cells (presumably by inducing apoptosis), but also kills non-infected tumor cells through a "bystander" effect. It is hypothesize that this bystander killin is mediated by both tumor- and host-specific mechanisms that involve humoral- and cell-mediated pathways. The overriding goal is to investigate the biology of AAV-P0-ICE mediated tumor destruction in the human and mouse schwannoma models we have developed in nude and immunocompetent mice, respectively, and to identify the molecular and cellular pathways mediating the killing of non-vector-infected tumor cells that is associated with apoptotic death of infected tumor cells. In brief, the specific aims are to 1) investigate the parameters of tumor regression in two schwannoma models in mice - a human schwannoma in nude mice and a mouse schwannoma in immune competent animals, 2) investigate whether caspase-1 bystander killing involves apoptotic death of uninfected cells, and 3) analyze whether host immune mechanisms are involved in AAV-P0-ICE initiated bystander killing. In vivo tumor growth will be monitored via bioluminescent imaging and MRI for the human and mouse schwannoma models, respectively; both techniques allow serial assessment over time in a given animal. A variety of biochemical and cell biological techniques will be used to determine whether caspase expressing tumor cells produce factors - both humoral and microvesicle contained - that can be transferred to and cause apoptotic death of uninfected tumor cells. Histological analysis and a variety of fundamental immunological assays will be used to investigate host mechanisms of bystander killing after AAV-P0-ICE injection. This application is novel and innovative in that it utilizes the first viral vector we know of that is restrictively expressed in Schwann-lineage cells hence allowing targeting of schwannomas without neurotoxicity, and proposes investigation of the pathways - tumor and host specific - which underlie induction of bystander tumor killing. Mechanistic understanding of the extensive and specific tumor killing induced by AAV-P0-ICE injection into schwannomas has the potential lead to novel treatment strategies for NF1, NF2 and schwannomatosis, as well as, a variety of other neoplasms.

描述（由申请人提供）：虽然神经鞘瘤肿瘤通常是良性的（非恶性的），但它们可能对患者造成毁灭性的后果。至于个别病人，往往没有有效的治疗方法。因此，神经鞘瘤治疗是一个主要的未满足的临床需求。我们已经开发了一种新的治疗方法，这些神经相关的肿瘤，涉及肿瘤内注射腺相关病毒（AAV）载体携带促凋亡基因caspase-1（ICE）下的Schwann细胞特异性启动子（P0），该载体被称为AAV-P0-ICE。我们的临床前研究已经显示AAV-P0- ICE载体产生肿瘤体积的延长减小而没有神经损伤的显著能力（提交的手稿）。我们的初步数据表明，AAV-PO-ICE不仅直接杀死感染的表达caspase-1的肿瘤细胞（可能是通过诱导凋亡），而且还通过“旁观者”效应杀死未感染的肿瘤细胞。据推测，这种旁观者杀伤是由肿瘤和宿主特异性机制介导的，涉及体液和细胞介导的途径。最重要的目标是研究我们分别在裸小鼠和免疫活性小鼠中开发的人和小鼠神经鞘瘤模型中AAV-P0-ICE介导的肿瘤破坏的生物学，并鉴定介导非载体感染的肿瘤细胞的杀伤的分子和细胞途径，所述非载体感染的肿瘤细胞与肿瘤细胞的凋亡性死亡相关。感染的肿瘤细胞简而言之，具体目的是1）研究小鼠中两种神经鞘瘤模型-裸鼠中的人神经鞘瘤和免疫活性动物中的小鼠神经鞘瘤中的肿瘤消退参数，2）研究半胱天冬酶-1旁观者杀伤是否涉及未感染细胞的凋亡性死亡，以及3）分析宿主免疫机制是否涉及AAV-PO-ICE引发的旁观者杀伤。将分别通过生物发光成像和MRI监测人和小鼠神经鞘瘤模型的体内肿瘤生长;两种技术均允许在给定动物中随时间进行连续评估。将使用各种生物化学和细胞生物学技术来确定表达半胱天冬酶的肿瘤细胞是否产生可以转移到未感染的肿瘤细胞并引起未感染的肿瘤细胞凋亡的因子-体液和微泡。将使用组织学分析和各种基础免疫学测定来研究AAV-P0-ICE注射后旁观者杀伤的宿主机制。该应用是新颖的和创新的，因为它利用了我们所知的第一种病毒载体，该病毒载体在许旺谱系细胞中限制性表达，因此允许靶向许旺细胞瘤而没有神经毒性，并提出了对途径的研究-肿瘤和宿主特异性-这是诱导旁观者肿瘤杀伤的基础。对AAV-P0-ICE注射到神经鞘瘤中诱导的广泛和特异性肿瘤杀伤的机制的理解有可能导致针对NF 1、NF 2和神经鞘瘤病以及各种其他肿瘤的新的治疗策略。