Translational Development of Replication-Competent Retrovirus Vectors

多形性胶质母细胞瘤(GBM)是成人最常见的原发脑肿瘤，与 尽管进行了积极的手术、放疗和化疗，但预后很差，只有12-15个月。这个 缺乏有效的治疗选择使这种疾病成为基因等新策略的目标 心理治疗。然而，基因治疗的唯一重大第三阶段临床试验，涉及使用 在GBM患者中，传统的复制缺陷逆转录病毒载体导致令人失望的低和 治疗上不足的转导水平仅为0.02%。标准的无能 因此，复制缺陷逆转录病毒载体在体内实现肿瘤的有效转导是一种 胶质瘤基因治疗的主要障碍。利用复制能力强的载体进行基因转移 效率会更高，因为每个成功转导的肿瘤细胞本身都会变成病毒- 产生细胞，即使在最初给药后仍维持进一步的转导事件。 我们先前已经证明，直接瘤内注射小鼠白血病病毒(MLV)- 基于复制能力的逆转录病毒(RCR)载体制剂可以实现非常有效的 胶质瘤中的自杀基因转移，其转导严格限于活跃分裂的肿瘤 没有明显扩散到肿瘤外部位的细胞，并导致显著延长 服用前药后存活，没有可检测到的全身副作用。 因此，在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 载体生物库(NGVB)，这里我们提出了优化和实现临床级RCR载体 生产和释放测试(目标1)，通过验证性测试重新验证这些临床级别的载体 FDA对至少2个来自不同物种的脑胶质瘤模型的治疗效果 规定，以及临床前毒理学和后续监测分析的重新确认为 FDA指南(目标2)授权的，并评估对流增强传递和非侵入性 核磁共振成像方法和开发临床试验方案(目标3)。我们建议执行这些任务 通过U01机制进行必要的临床前翻译研究，最终目标是提交 IND并获得FDA的批准以启动临床试验。 相关性(请参阅说明)： 多形性胶质母细胞瘤(GBM；WHO IV级恶性胶质瘤)是最常见的恶性类型 成人脑肿瘤，占原发脑肿瘤的50%-60%，占儿童颅内肿瘤的7%-10% 肿瘤。尽管在神经成像、神经外科、放射治疗和支持性护理方面取得了重大进展， GBMS的总体预后仍只有12-15个月，目前的治疗仅能延缓复发。 因此，有一种尚未得到满足的需求，即开发有效的新方法来对抗这种毁灭性的疾病。

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. Therefore, in collaboration with neurosurgery groups at UCLA, USC, and UCSF, and the National Gene Vector Biorepository (NGVB), here we propose to optimize and implement clinical grade RCR vector production and release testing (Aim 1), to re-validate these clinical grade vectors by confirmatory testing of therapeutic efficacy in at least 2 intracranial glioma models from different species per FDA stipulations, as well as re-validation of preclinical toxicology and follow-up monitoring assays as mandated by FDA guidelines (Aim 2), and to evaluate convection-enhanced delivery and non-invasive NMR imaging methodologies and develop clinical trial protocols (Aim 3). 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. RELEVANCE (See instructions): Glioblastoma multiforme (GBM; WHO Grade IV malignant glioma), is the most common form of malignant brain tumor in adults, accounting for 50-60% of primary brain tumors, and 7-10% of childhood intracranial neoplasms. Despite major improvements in neuroimaging, neurosurgery, radiotherapy, and supportive care, the overall prognosis for GBMs is still only 12-15 months, and current treatments only delay recurrence. Hence, there is an unmet need to develop effective new approaches against this devastating disease.