NeuroD/betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice

第一代腺病毒(FGAd)介导的同源盒基因PDX-1的转移可诱导链脲佐菌素(STZ)诱导的糖尿病小鼠肝脏胰岛素分泌和一过性低血糖。不同于FG-ADS的作用是短暂的，依赖助手(HD)的ADS产生长期的转基因表达。我们使用HDAd将PDX-1转导给STZ小鼠，观察到PDX-1的外分泌分化作用导致的高血糖的部分改善，但由于胰酶的表达而引起的严重的、致死性的肝炎。HDAD介导的神经D是PDX-1下游的一种发育因子，在不引发肝炎的情况下部分逆转了STZ小鼠的高血糖。向Neurd添加胰岛生长因子β细胞蛋白完全纠正了糖尿病。在实验期间(&gt；120天)，治疗的小鼠是健康的，血糖正常。我们在肝脏中检测到胰岛素和其他胰岛特异性转录物，包括胰岛素原加工酶、β细胞特异性葡萄糖激酶和磺脲受体。免疫组织化学显示胰岛素、胰升糖素、胰多肽(PP)和生长抑素产生细胞排列成胰岛簇，免疫电子显微镜下可见典型的胰岛素特异性颗粒。我们的数据表明，NeuD/Betacellin是治疗胰岛素依赖型糖尿病的一种很有前途的基因治疗方案。这些结果发表在NAT上。Med 9,596,2003和许多评论文章，如出版记录所示。

First-generation adenovirus(FGAd)-mediated transfer of the homeobox gene Pdx-1 was reported to induce hepatic insulin production and transient hypoglycemia in streptozotocin(STZ)-treated diabetic mice. Unlike FG-Ads whose effects are short-lived, helper-dependent(HD) Ads produce prolonged transgene expression. We used HDAd to deliver Pdx-1 to STZ mice and observed partial amelioration of hyperglycemia, but severe, fatal, hepatitis, caused by expression of trypsin, resulting from the exocrine-differentiating action of Pdx-1. HDAd-mediated transfer of NeuroD, a developmental factor downstream of Pdx-1,partially reversed the hyperglycemia of STZ mice without inducing hepatitis. The addition of an islet growth factor betacellulin to NeuroD completely corrected the diabetes. Treated mice were healthy and normoglycemic for the duration of the experiment (>120 days). We detected in the liver insulin and other islet-specific transcripts, including proinsulin-processing enzymes, beta cell-specific glucokinase, and sulfonylurea receptor. Immunohistochemistry revealed the presence of insulin, glucagon, pancreatic polypeptide(PP) and somatostatin-producing cells organized into islet clusters, and immuno-electron microscopy showed typical insulin-specific granules. Our data suggest that NeuroD/betacellulin is a promising gene therapy regimen for the treatment of insulin-dependent diabetes. These results were published in Nat. Med 9,596,2003 and many review articles as shown in the publication records.