REPLICONS ENCODING SUICIDE GENES AS THERAPIES FOR GLIOMA

尽管近年来传统的手术、放射和化学疗法取得了进展，但恶性胶质瘤患者的预后仍然很差。神经胶质瘤的新型自杀基因疗法在临床前研究中显示出前景；然而，发展有效的交付系统对于确保其成功至关重要。我们认为，由于其在体内的瞬时特性、蛋白质表达的快速开始、无法在宿主中传播或引起疾病，以及在复制周期中缺乏DNA中间体，从而消除了插入突变的可能性，因此，基于rna的封装复制子是一种有吸引力的替代载体，可以用于这些治疗。在这个I期应用中，我们建议在小鼠模型系统中测试使用表达疱疹病毒胸苷激酶、嘌呤核苷磷酸化酶或胞嘧啶脱氨酶的复制子载体进行胶质瘤自杀基因治疗的效果。这些载体将被单独评估或组合评估，以确定最能促进肿瘤生存和抑制肿瘤生长的基于复制的自杀基因鸡尾酒。这些研究采用了相关的脑肿瘤小鼠模型系统，并应形成II期提案的基础，目标是将封装的复制子作为脑肿瘤治疗的载体推向市场。传统的治疗恶性胶质瘤的方法收效甚微，被诊断为这些肿瘤的患者平均存活时间不到一年。考虑到每年有15,000名美国人被诊断出患有这些肿瘤，导致11,000人死亡，因此需要有效的治疗方法。我们相信，封装复制子编码自杀基因是一种有前景的、具有巨大商业潜力的新型治疗方法。

The prognosis for patients diagnosed with malignant glioma has remained very poor despite recent advances in traditional surgical, radiation, and chemical therapies. Novel suicide gene therapies for gliomas have shown promise in pre-clinical studies; however, the development of effective delivery systems is critical to ensure their success. We believe that encapsidated RNA-based replicons are an attractive alternative vector to the traditional ones being pursued for these treatments because of their transient nature in vivo, rapid onset of protein expression, inability to spread or cause disease in the host, and lack of DNA intermediates in the replication cycle, which eliminates the possibility of insertional mutagenesis. In this phase I application, we propose to test the efficacy of using replicon vectors that express herpesvirus thymidine kinase, purine nucleoside phosphorylase, or cytosine deaminase for suicide gene therapy of gliomas in mouse model systems. These vectors will be evaluated alone and in combinations to identify the replicon-based suicide gene cocktail that best promotes survival and inhibition of tumor growth. These studies employ relevant mouse model systems for brain tumors and should form the foundation of a Phase II proposal with the goal of bringing encapsidated replicons to the marketplace as a vector for brain tumor therapies. PROPOSED COMMERCIAL APPLICATION Traditional therapies for malignant gliomas have met with little success, and patients diagnosed with these tumors survive for less than one year on average. Considering that 15,000 Americans are diagnosed with these tumors annually, resulting in 11,000 deaths, effective treatments are needed. We believe that encapsidated replicons encoding suicide genes are a promising, novel treatment with great commercial potential.