Translational Development of Replication-Competent Retrovirus Vectors

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，但预后仅为12-15个月。的 由于缺乏有效的治疗选择，这种疾病已成为新策略的目标， 疗法然而，唯一一个主要的基因治疗III期临床试验，涉及使用 传统的复制缺陷型逆转录病毒载体在GBM患者中， 治疗上不充分的转导水平仅为约0.02%。标准的无能 因此，复制缺陷型逆转录病毒载体在体内实现肿瘤的有效转导是一种有效的方法。 神经胶质瘤基因治疗的主要障碍。复制型载体在基因转移中的应用 将更有效，因为每个成功转导的肿瘤细胞本身将成为病毒- 产生细胞，甚至在初始施用后维持进一步的转导事件。 我们以前已经证明，直接瘤内注射小鼠白血病病毒（MLV）- 基于可复制逆转录病毒（RCR）载体的制备可以实现非常高效的 胶质瘤中的自杀基因转移，转导严格限制在活跃分裂的肿瘤中 细胞没有明显扩散到瘤外部位的证据，并导致显著延长 前药给药后的存活率，而没有可检测到的全身副作用。 因此，与加州大学洛杉矶分校、南加州大学、加州大学旧金山分校和国家基因组的神经外科小组合作， 载体生物库（NGVB），在这里，我们建议优化和实施临床级RCR载体 生产和放行检测（目标1），通过确证性检测重新验证这些临床级载体 根据FDA，在至少2种不同种属的颅内胶质瘤模型中的治疗有效性 规定，以及临床前毒理学和后续监测试验的重新验证， FDA指南（目标2）要求，并评估对流增强输送和非侵入性 NMR成像方法和制定临床试验方案（目标3）。我们建议执行这些 通过这种U 01机制进行必要的临床前转化研究，最终目标是提交一份 IND并获得FDA批准启动临床试验。 相关性（参见说明）： 多形性胶质母细胞瘤（GBM; WHO IV级恶性胶质瘤）是恶性胶质瘤的最常见形式。 成人脑肿瘤，占原发性脑肿瘤的50-60%，儿童颅内肿瘤的7-10%。 肿瘤。尽管在神经影像学、神经外科、放射治疗和支持治疗方面有了重大改进， GBM的总体预后仍然仅为12-15个月，并且目前的治疗仅延迟复发。 因此，开发针对这种毁灭性疾病的有效新方法的需求尚未得到满足。

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.