Induced islet neogenesis therapy in vivo

描述（申请人提供）：尽管开发了促进胰岛素分泌或降低胰岛素抵抗的口服降糖药，以及具有广泛变化的作用持续时间的不同形式的胰岛素，并且出现了显著改进的胰岛移植方案，但胰岛素缺乏型糖尿病的治疗仍然不令人满意。实验性基因疗法正在探索作为一种可能的选择，以改善治疗或潜在的“治愈”的疾病。主要研究者最近开发的一种有前途的基因治疗策略是通过向糖尿病小鼠的肝脏递送胰岛特异性转录因子来诱导胰岛新生。我们使用辅助依赖性腺病毒（HDAd）将转录因子NeuroD/Beta2（ND/B2）和胰岛生长因子β细胞素（Btc）递送至链脲佐菌素糖尿病小鼠的肝脏。作为对治疗的反应，小鼠在肝脏中形成了新的胰岛，并在葡萄糖耐量试验（GTT）期间形成了正常的血糖和胰岛素水平。治疗逆转了这些小鼠的糖尿病超过四个月，实验持续时间。治疗中观察到的毒性可忽略不计。在R21申请中，我们提出在非人灵长类动物模型中探索使用类似的策略来治疗糖尿病。有两个具体目标：1。使用链脲佐菌素（STZ）治疗在狒狒中建立胰岛素缺乏型糖尿病模型。2.使用基于球囊导管的方法向STZ诱导的糖尿病狒狒的肝脏中递送含有胰岛特异性转录因子Neurogenin 3（Ngn 3）和胰岛生长因子Etc的HDAd以诱导胰岛新生，目的是逆转狒狒的糖尿病。初步实验表明，Ngn 3产生更好的结果比ND/？2.在狒狒中进行的其他试点实验使我们能够开发基于球囊导管的方案，以高剂量直接向肝脏递送HDAs，而没有显著的全身性传播或毒性。该方案将避免当载体全身施用时观察到的HDAs的实质性毒性。这些目标是基于有据可查的初步实验。如果这种治疗策略能改善狒狒的糖尿病，而没有明显的毒副作用，那么它将是一个重要的原理验证实验，为未来可能的临床试验铺平道路。

DESCRIPTION (provided by applicant): Despite the development of oral hypoglycemic agents that boost insulin secretion or reduce insulin resistance, and of different forms of insulin with widely varying durations of action, and the advent of a markedly improved protocol for islet transplantation, the treatment of insulin-deficient diabetes remains unsatisfactory. Experimental gene therapy is being explored as a possible option for an improved treatment or potentially a "cure" for the disease. A promising gene therapy strategy that was recently developed by the Principal Investigator is that of induced islet neogenesis by the delivery of islet-specific transcription factor to the liver of diabetic mice. We used a helper-dependent adenovirus (HDAd) to deliver a transcription factor, NeuroD/Beta2 (ND/B2), and an islet growth factor, betacellulin (Btc), to the liver of streptozotocin diabetic mice. In response to the treatment, the mice formed new pancreatic islets in the liver and developed normal blood glucose and insulin levels during a glucose tolerance test (GTT). The treatment reversed the diabetes of these mice for over four months, the duration of the experiment. There was negligible toxicity observed for the treatment. In this R21 application we propose to explore the use of a similar strategy to treat diabetes in a non-human primate model. There are 2 specific aims: 1. to establish an insulin-deficient diabetes model in baboons using streptozotocin (STZ) treatment. 2. To use a balloon catheter-based method to deliver into the liver of STZ-induced diabetic baboons HDAd containing the islet-specific transcription Neurogenin 3 (Ngn3) and the islet growth factor Etc to induce islet neogenesis with the objective of reversing the diabetes of baboons. Preliminary experiments show that Ngn3 produces even better results than ND/?2. Other pilot experiments in baboons have allowed us to develop the balloon catheter-based protocol to deliver HDAds at a high dose directly to the liver without significant systemic dissemination or toxicity. This protocol would circumvent the substantial toxicity of HDAds that is observed when the vector is administered systemically. These aims are based on well documented preliminary experiments. If the treatment strategy ameliorates diabetes in baboons without significant toxic side effects, then it will be an important proof-of-principle experiment that will pave the way for possible clinical trials in the future.