We have read with great interest and excitement the article by Wang et al ,1 in which the authors demonstrated that pancreatic overexpression of the human trypsin inhibitor SPINK1 (serine protease inhibitor Kazal type 1, also known as pancreatic secretory trypsin inhibitor) via an adeno-associated viral (AAV) vector significantly improved pancreatitis severity and outcomes in preclinical mouse models.1 This seminal study provides proof of concept that AAV-mediated delivery of trypsin inhibitors to the pancreas is a viable strategy for the treatment of pancreatitis and/or prevention of recurrent attacks. A limitation of the approach, however, is the relatively low expression levels of SPINK1 attainable in the pancreas. In the cited study, pancreatic trypsin-inhibitory activity and SPINK1 protein levels were elevated only by 1.4-fold and 1.6-fold, respectively, after viral transduction. Further increases in the viral dose employed may not be feasible due to cost and higher risk of side effects. Here, using a cell culture model, we demonstrate that introducing a short intronic sequence into the human SPINK1 coding DNA (cDNA) resulted in dramatic increases in mRNA and protein expression levels. Studies conducted in a variety of eukaryotes showed that introns can boost gene expression, a phenomenon referred to as intron-mediated enhancement.2 …

中文翻译：

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内含子介导的 SPINK1 表达增强用于胰腺炎治疗


我们怀着极大的兴趣和兴奋阅读了 Wang 等人的文章，1 其中作者证明，在临床前小鼠模型中，通过腺相关病毒 （AAV） 载体过表达人胰蛋白酶抑制剂 SPINK1（丝氨酸蛋白酶抑制剂 Kazal 1 型，也称为胰腺分泌胰蛋白酶抑制剂）可显著改善胰腺炎的严重程度和预后。胰腺是治疗胰腺炎和/或预防复发的可行策略。然而，该方法的一个局限性是胰腺中可达到的 SPINK1 表达水平相对较低。在引用的研究中，病毒转导后胰蛋白酶抑制活性和 SPINK1 蛋白水平分别仅升高了 1.4 倍和 1.6 倍。由于成本和更高的副作用风险，进一步增加所采用的病毒剂量可能不可行。在这里，使用细胞培养模型，我们证明将短内含子序列引入人类 SPINK1 编码 DNA （cDNA） 会导致 mRNA 和蛋白质表达水平显着增加。对多种真核生物进行的研究表明，内含子可以促进基因表达，这种现象被称为内含子介导的增强。