Translational Development of Replication-Competent Retrovirus Vectors

具有复制能力的逆转录病毒载体的转化开发

基本信息

批准号：
8077255
负责人：
NORIYUKI KASAHARA
金额：
$ 91.4万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8077255
关键词：
Adult Adverse effects Basic Science Biodistribution Biological Assay Blood Tests Bolus Infusion Bone Marrow Brain Canis familiaris Cells Chemistry Clinical Clinical Protocols Clinical Trials Clinical trial protocol document Collaborations Consensus Convection Critical Pathways Cryopreservation Detection Development Disease Documentation Dose Event Flow Cytometry Flucytosine Fluorouracil Gene Transfer Genes Glioblastoma Glioma Goals Guidelines Harvest Histopathology Human Image Immune response Immunocompetent Immunohistochemistry Injection of therapeutic agent Institutional Review Boards Intracranial Neoplasms Intravenous Laboratories Magnetic Resonance Imaging Measurement Mediating Methodology Methods Modeling Molecular Analysis Monitor Murine leukemia virus NMR Spectroscopy Nori Normal tissue morphology Nude Mice Patients Phase III Clinical Trials Plasmid Cloning Vector Plasmids Preparation Primary Brain Neoplasms Principal Investigator Procedures Prodrugs Production Protocols documentation Publishing Radiosurgery Rattus Reagent Recovery Research Research Personnel Retroviral Vector Retroviridae Risk Rodent Safety Serum Signal Transduction Site Spleen Sterility Testing The Sun Therapeutic Time Tissue Sample Toxic effect Toxicology Transfection Treatment Efficacy Validation Vial device Virus Wolves Xenograft procedure base calcium phosphate precipitation cell bank chemotherapy design effective therapy follow-up gene therapy gene transfer vector genotoxicity improved in vivo killings neoplastic cell neurosurgery organizational structure outcome forecast pre-clinical process optimization programs reagent standard scale up subcutaneous suicide gene translational study tumor vector

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, is associated with a dismal prognosis of only 12-15 months despite aggressive surgery, radiation, and chemotherapy. The lack of effective treatment options has made this disease a target for new strategies such as gene therapy. However, the only major Phase III clinical trial of gene therapy, involving the use of conventional replication-defective retrovirus vectors in GBM patients, resulted in disappointingly low and therapeutically inadequate transduction levels on the order of only 0.02%. The inability of standard replication-defective retroviral vectors to achieve effective transduction of tumors in vivo is therefore a major obstacle to gene therapy for gliomas. The use of replication-competent vectors for gene transfer would be more efficient, as each tumor cell that is successfully transduced would itself become a virus-producing cell, sustaining further transduction events even after initial administration. We have previously demonstrated that direct intratumoral injection of murine leukemia virus (MLV)-based replication-competent retrovirus (RCR) vector preparations can achieve tremendously efficient suicide gene transfer in gliomas, with transduction stringently restricted to the actively dividing tumor cells without evidence of significant spread to extratumoral sites, and resulting in significantly prolonged survival upon prodrug administration, without detectable systemic side effects. In collaboration with neurosurgery groups at UCLA, USC, and UCSF, and the National Gene Vector Laboratory (NGVL), here we propose to develop and implement clinical grade RCR vector production (Aim 1), to validate these clinical grade vectors by confirmatory testing of therapeutic efficacy in rodent intracranial glioma models, and in larger canine models (Aim'2), to optimize monitoring methodologies as mandated by FDA guidelines, and to develop clinical trial protocols (Aim 3). Hence, we propose to perform these necessary preclinical translational studies through this U01 mechanism, with the final goal of filing an IND and obtaining approval from the FDA to initiate clinical trials.

描述（由申请人提供）：多形性胶质母细胞瘤 (GBM) 是成人中最常见的原发性脑肿瘤，尽管进行了积极的手术、放疗和化疗，但其预后仅为 12-15 个月。由于缺乏有效的治疗方案，这种疾病成为基因治疗等新策略的目标。然而，基因治疗的唯一主要 III 期临床试验，涉及在 GBM 患者中使用传统的复制缺陷型逆转录病毒载体，结果令人失望地低且治疗不足的转导水平仅为 0.02%。因此，标准复制缺陷型逆转录病毒载体无法实现体内肿瘤的有效转导，这是神经胶质瘤基因治疗的主要障碍。使用具有复制能力的载体进行基因转移会更有效，因为成功转导的每个肿瘤细胞本身都会成为病毒产生细胞，即使在初次施用后也能维持进一步的转导事件。我们之前已经证明，直接瘤内注射基于鼠白血病病毒（MLV）的具有复制能力的逆转录病毒（RCR）载体制剂可以在神经胶质瘤中实现极其有效的自杀基因转移，转导严格限制在活跃分裂的肿瘤细胞中，而没有证据表明其具有显着的效果。扩散到肿瘤外部位，并导致前体药物给药后生存期显着延长，且没有可检测到的全身副作用。与加州大学洛杉矶分校、南加州大学和加州大学旧金山分校的神经外科小组以及国家基因载体实验室 (NGVL) 合作，我们建议开发和实施临床级 RCR 载体生产（目标 1），通过验证性测试来验证这些临床级载体啮齿类动物颅内神经胶质瘤模型和大型犬类模型的治疗效果（目标 2），根据 FDA 指南优化监测方法，并制定临床试验方案（目标 3）。因此，我们建议通过U01机制进行这些必要的临床前转化研究，最终目标是提交IND并获得FDA批准启动临床试验。