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首页> 外文期刊>Gene Therapy and Molecular Biology >Hepatitis Virus Protein X-PhenylalanineHydroxylase fusion proteins identified in PKU micetreated with AAV-WPRE vectors
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Hepatitis Virus Protein X-PhenylalanineHydroxylase fusion proteins identified in PKU micetreated with AAV-WPRE vectors

机译：在AAV-WPRE载体治疗的PKU小鼠中鉴定出的肝炎病毒蛋白X-苯丙氨酸羟化酶融合蛋白

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Utilizing the Pahenu2 mouse model for phenylketonuria (PKU), we developed an improved expression vector containing the Woodchuck Hepatitis Virus post-transcriptional regulatory element inserted into a rAAV-mPAH construct (rAAV-mPAH-WPRE) for treatment of PKU. Following portal vein delivery of these vectors to Pahenu2 mice, we observed the unintentional development of neoplastic disease (44%) and hepatic pathology (70%) in WPRE-treated mice. Our vector contained a portion of the oncogenic hepadnoviral “X-protein” in the WPRE segment that had been intentionally modified in an attempt to prevent its expression. The hepadnoviral X- protein encoding sequence is known to function as a mediator in oncogenic activity (Murakami, 1999). We have evidence that the X-protein fragment unexpectedly formed a fusion protein with a phenylalanine hydroxylase transgene in our vector and suspect this fusion protein may have been responsible for the high rate of unusual types of cancer and hepatic pathology. These results are not to imply that the use of the WPRE element will always result in the development of cancer. But in this particular instance, an unanticipated event may have ensued when the X-protein formed a fusion protein with the transgene. This is a cautionary illustration to be considered when developinggenetic therapies to treat diseases.
机译：利用针对苯丙酮尿症（PKU）的Pahenu2小鼠模型，我们开发了一种改良的表达载体，其中包含插入到rAAV-mPAH构建体（rAAV-mPAH-WPRE）中的土拨鼠肝炎病毒转录后调控元件，用于治疗PKU。在将这些载体门静脉递送给Pahenu2小鼠后，我们观察到在WPRE治疗的小鼠中肿瘤性疾病（44％）和肝病理（70％）的意外发展。我们的载体在WPRE片段中含有部分致癌性肝癌细胞“ X蛋白”，并对其进行了有意修饰以阻止其表达。已知肝上皮性X-蛋白编码序列在致癌活性中起中介作用（Murakami，1999）。我们有证据表明，X蛋白片段在我们的载体中意外地与苯丙氨酸羟化酶形成了融合蛋白，并怀疑该融合蛋白可能是导致异常类型癌症和肝病理的高发生率的原因。这些结果并不意味着使用WPRE元素将始终导致癌症的发展。但是在这种特定情况下，当X蛋白与转基因形成融合蛋白时，可能会发生意料之外的事件。这是在开发用于治疗疾病的遗传疗法时应考虑的警告提示。

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