Targeted Gene Therapy Using Synthetic Vectors

描述(申请人提供)：基因疗法是治疗源于遗传疾病(如癌症)的人类疾病的一种很有前途的方法。然而，作为一种可行的治疗方式，基因治疗应用的一个主要障碍是开发安全有效的基因转移载体。病毒和非病毒(合成)载体都在积极研究中。到目前为止，对病毒载体的研究远远多于对合成载体的研究。然而，随着研究的进展，合成载体呈现出比病毒载体更多的优势。这项工作的目标是开发一种新的非病毒的、靶向的、用于肿瘤疾病基因治疗的基因转移载体。对于第一阶段的原则证明，我们选择叶酸作为叶酸受体表达卵巢癌细胞模型的靶向部分进行体外实验。我们的新型基因转移载体将通过进行一系列体外评估来评估其在卵巢癌治疗中的潜在作用，以确定载体的特征并确定两个报告基因的相对基因转移效率。我们将筛选DNA缩合、复合体稳定性和体外基因转移的载体。卵巢癌是美国第二常见也是最致命的妇科恶性肿瘤。根据美国癌症协会的数据，卵巢癌以每年约23,000例新病例的频率发生，存活率不到50%。由于早期发现的困难和疾病的渐进性，现有的卵巢癌治疗方法的成功率有限。单独使用或与其他治疗方法联合使用的基因疗法，为有效控制传统治疗方案难以治愈的癌症提供了新的希望。这里提出的一种新的癌症靶向基因转移剂，基于纳米颗粒类脂质支架，将是日益增长的癌症治疗方法的一个受欢迎的补充。

DESCRIPTION (provided by applicant): Gene therapy is a promising approach for treatment of human diseases rooted in genetic disorders (e.g., cancer). However, a major obstacle in the application of gene therapy as a viable treatment modality is the development of safe and effective gene transfer vectors. Both viral and non-viral (synthetic) vectors are actively being studied. To date, viral vectors have been studied much more than synthetic vectors. However, as research progresses, synthetic vectors are presenting themselves with several advantages over viral vectors. The goal of this proposed effort is to develop a new non-viral, targeted, gene transfer vector for gene therapy of neoplastic diseases. For the Phase I proof-of-principle, we have chosen folic acid as a targeting moiety for folate receptor expressing ovarian cancer cell model for in vitro experiments. Our novel gene transfer vectors will be evaluated for the potential treatment of ovarian cancer by conducting a series of in vitro assessments to characterize the vectors and determine the relative gene transfer efficiency of two reporter genes. We will screen vectors for DNA condensation, complex stability, and in vitro gene transfer. Ovarian cancer is the second most common and the deadliest gynecologic malignancy in the US. According to the American Cancer Society, ovarian cancer occurs at a frequency of ~23,000 new cases per year with a less than 50% survival rate. Existing treatment modalities for ovarian cancer have limited success rates due to difficulties in early detection and the progressive nature of the disease. Gene therapy, either used alone or in combination with other therapeutic modalities, provides new promises for effective control of cancers that are refractory to conventional therapeutic regimens. A new cancer-targeting gene tranfer agent based on a nanoparticle lipid-like scaffold as proposed here would be a welcome addition to the growing arsenal of cancer therapies.