Translational Development of Replication-Competent Retrovirus Vectors

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患者中使用常规的复制缺陷型逆转录病毒载体，导致仅0.02%的数量级的令人不安的低和治疗上不充分的转导水平。因此，标准的复制缺陷型逆转录病毒载体不能在体内实现肿瘤的有效转导是神经胶质瘤基因治疗的主要障碍。使用可复制载体进行基因转移将更有效，因为成功转导的每个肿瘤细胞本身将成为产生病毒的细胞，甚至在初始施用后维持进一步的转导事件。我们先前已经证明，直接瘤内注射基于鼠白血病病毒（MLV）的可复制逆转录病毒（RCR）载体制剂可以在神经胶质瘤中实现非常有效的自杀基因转移，转导严格限于活跃分裂的肿瘤细胞，而没有证据表明显著扩散到瘤外部位，并且导致前药给药后显著延长的生存期，而不会产生可检测到的全身副作用。与UCLA、USC和UCSF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（Aim 1），通过在啮齿动物颅内胶质瘤模型和大型犬模型（Aim 2）中的疗效验证测试来验证这些临床级载体，以优化FDA指南规定的监测方法，并制定临床试验方案（目标3）。因此，我们建议通过U 01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批准以启动临床试验。

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.