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Gene Therapies for Cancer: Strategies. Challenges and Successes

机译:基因治疗癌症:策略。和成功

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Gene therapy in a globa! context involves correction of a genetic defect by introducing a normal version of a defective or missing gene thereby correcting an underlying disorder (Friedmann, 1992). Milestones on the path of developing gene therapies are presented in Figure I. This concept was first advanced in the 1960s after observing that viruses could cause malignant transformation in cells by integrating their genetic information into the genomes of infected cells. In 1966, Edward Tatum proposed the use of viruses in the genetic manipulation of somatic cells and its possible therapeutic applications (Tatum, 1966). A few years later, initial proof-of-concept for gene therapy was demonstrated using tobacco mosaic virus as a vector to introduce a polyadenylate stretch to viral RNA (Rogers and Ffuderer, 1968). Encouraged by these results, gene therapy was attempted in the 1970s to correct a urea cycle disorder by administering wild type Shope papilloma virus, encoding the arginase gene, to two severely handicapped young girls suffering from hyperarginemia (Rogers et al., 1973; Terheggen et al., 1975). Unfortunately, the desired outcome was not achieved. The first successful therapeutic application of this gene therapy approach was evident in 1990 when a retrovirus-vector was used to mediate transfer of the gene encoding adenosine deaminase (ADA) into the T-cells of two children suffering from severe combined immunodeficiency (SCID) (Rosenberg et al., 1990). The response was positive for only one of the patients; however, debate arose since the patient simultaneously received enzyme replacement therapy alongside gene therapy. Another study was conducted in an 18-year-old patient suffering from ornithine transcarbamylase deficiency, a relatively mild form of nitrogen metabolism disorder. However, the application of gene therapy in patients was temporarily halted following the death of a patient due to vector-associated toxicity (Stolberg, 1999).
机译:基因治疗在世界人口!通过引入纠正基因缺陷正常版本的缺陷或缺失的基因从而纠正一个潜在的障碍(弗里德曼,1992)。发展基因疗法呈现在图即这一概念最早在1960年代先进观察后,病毒可能导致恶性转化细胞中通过集成他们的基因组的遗传信息受感染的细胞。病毒的基因操作的使用体细胞及其可能的治疗应用程序(泰特姆,1966)。初始概念验证基因疗法演示了使用烟草花叶病毒向量引入polyadenylate伸展病毒RNA(罗杰斯和Ffuderer, 1968)。通过这些结果,基因治疗是尝试1970年代的尿素循环障碍管理野生型Shope乳头状瘤病毒精氨酸酶基因编码,两个严重的年轻女孩遭受hyperarginemia(罗杰斯等人,1973年;, 1975)。没有实现。这种基因疗法的治疗应用在1990年,一位方法明显逆转录病毒载体用于中介转让基因编码腺苷脱氨酶(ADA)两个孩子患有严重的t细胞联合免疫缺陷(SCID)(罗森博格等人, 1990)。一个病人;病人同时接受酶替代治疗与基因治疗。另一项研究是在一个18岁的进行的鸟氨酸氨甲酰基转移酶的病人缺乏一种相对温和的氮新陈代谢障碍。基因治疗的病人被暂时停止死后的病人由于vector-associated毒性(谢尔,1999)。

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