Low-cost proinsulin-transferrin fusion protein in rice for treatment of diabetes

描述（由申请人提供）：糖尿病已成为一种毁灭性的流行病在世界范围内。胰岛素由于其控制血糖水平的能力而通常用作帮助管理糖尿病的治疗方法，并且在全球范围内需求量很大，但它面临多种挑战，包括不良代谢副作用，体内药物寿命短和成本高。今天，数百万人继续遭受糖尿病及其相关病症的折磨并死于糖尿病及其相关病症。因此，迫切需要开发新的、廉价的降血糖剂来治疗和阻止这种使人衰弱的疾病的快速传播。重组胰岛素原转铁蛋白（ProINS-Tf）融合蛋白最近被发现，以促进增强和持续的体内降血糖疗效相比，胰岛素。虽然这种融合蛋白作为一种新的肝特异性降血糖剂，可以克服胰岛素的一些缺点，它的治疗用途是很有希望的，目前在经济上是不可行的，由于低产量和高成本与其生产的哺乳动物细胞系。为了获得ProINS-Tf的所有好处，同时降低其供应成本，Ventria Bioscience及其南加州大学的合作者正在利用各自的专业知识在水稻中表达ProINS-Tf嵌合蛋白，然后评估其作为新型降血糖剂的生物活性。这个拟议的项目有三个相关的具体目标。在目标1中，Ventria将使用其专有的表达技术，用ProINS与Tf融合的嵌合基因构建体转化水稻植物，并将产生表达ProINS-Tf的转基因植物。在目标2中，Ventria将进行表达筛选分析，以鉴定具有最高水平ProINS-Tf表达的转基因事件，然后进行蛋白纯化。在目标3中，南加州大学的Ventria合作者将通过体外细胞培养试验证实ProINS-Tf的生物活性。这些研究的目的是开发一种新的和负担得起的肝细胞前药用于治疗糖尿病。这些研究对NIH促进人类健康和降低医疗费用的使命具有重要意义。

DESCRIPTION (provided by applicant): Diabetes has become a devastating epidemic worldwide. Insulin is commonly used as a treatment to help manage diabetes because of its ability to control blood glucose levels, and is in high demand worldwide, but it faces multiple challenges including adverse metabolic side-effects, short in vivo pharmaceutical life, and high cost. Today, millions of people continue to suffer and die from diabetes and its related conditions. Therefore, there is an urgent need to develop novel, inexpensive hypoglycemic agents to treat and arrest the fast spreading of this debilitating disease. A recombinant proinsulin-transferrin (ProINS-Tf) fusion protein was recently found to facilitate an enhanced and sustained in vivo hypoglycemic efficacy compared to insulin. While this fusion protein holds great promise as a novel hepato-specific hypoglycemic agent that can overcome some of the disadvantages of insulin, its therapeutic use is currently economically unfeasible due to low yields and high costs associated with its production in mammalian cell lines. In an effort to capture all the benefits of ProINS-Tf while lowering its supply cost, Ventria Bioscience and its collaborators at the University of Southern California are building on their respective expertise t express a ProINS-Tf chimeric protein in rice, and then assess its biological activities related to its usage as a novel hypoglycemic agent. This proposed project has three related specific aims. In Aim 1, Ventria will use its proprietary expression technology to transform rice plants with a chimeric gene construct composed of ProINS fused to Tf and will produce transgenic plants expressing ProINS-Tf. In Aim 2, Ventria will perform expression screening analysis to identify the transgenic events with the highest level expression of ProINS-Tf followed by protein purification. In Aim 3, Ventria's collaborators at the University of Southern California will confim the biological activities of ProINS-Tf through in vitro cell culture assays. The aims of these studies are to develop a novel and affordable hepatocyte prodrug for the treatment of diabetes. These studies are significant and relevant to the mission of the NIH to promote human health and reduce health care costs.