Development of DT-110 as an oral therapeutic for type 2 diabetes

 描述(申请人提供)：2型糖尿病是一种慢性衰弱疾病，有可能在2030年达到大流行水平。目前全球有近3.5亿人受到糖尿病的影响，超过70%的2型糖尿病患者死于心血管疾病。然而，到目前为止，还没有特定的糖尿病药物被认为在将与2型糖尿病相关的心血管疾病的风险降至最低方面具有优势。因此，开发同时降低心血管疾病风险的新型抗糖尿病药物将是非常可取和必要的。正在开发的产品是DT-110，一种三肽，用于治疗2型糖尿病的口服疗法。技术创新是将三肽作为口服剂型应用于治疗人类疾病。在我们的第一阶段研究中，我们发现DT-110激活了G蛋白偶联受体D(MRGprD)信号通路，这一信号通路尚未被报道与代谢性疾病有关。由于MRgprD的激活对心血管系统具有保护作用，我们的结果提示，DT-110除了控制血糖水平外，还可能对心血管系统产生有益的影响，因此，DT-110可能是一种潜在的抗糖尿病药物，可以将2型糖尿病相关心血管疾病的风险降至最低。这项SBIR的长期目标是完成DT-110的临床前研究，提交IND，并将其作为能够降低与2型糖尿病相关的心血管疾病风险的新型抗2型糖尿病药物进行商业化。DT-110的作用机制与目前治疗2型糖尿病的药物不同。在第二阶段研究中，我们将验证DT-110专门作用于这一新的信号通路以有效降低2型糖尿病患者的血糖水平和保护心血管系统的假设。这一第二阶段SBIR的具体目标是1)研究DT-110在转基因小鼠控制血糖水平和调节血管扩张方面的治疗作用，2)开发肠道包衣DT-110，以及3)在大型动物模型中确定DT-110的降血糖效果。这项研究将为我们理解DT-110的新作用机制以及它在各种动物模型中支持IND提交的有效性提供重要信息，并最终 导致成功开发一种治疗2型糖尿病的新药，该药物可能对心血管系统也有保护作用。

 DESCRIPTION (provided by applicant): Type 2 diabetes is a chronic debilitating disease that threatens to reach pandemic level by 2030. Nearly 350 million people worldwide are currently affected by diabetes and more than 70% of patients with type 2 diabetes die of cardiovascular causes. However, no particular diabetes medication to date is considered superior in the minimization of the risk of cardiovascular diseases associated with type 2 diabetes. Therefore, development of new anti-diabetic drugs that also decreases the risk of cardiovascular diseases will be highly desirable and needed. The product being developed is DT-110, a tripeptide, as an oral therapeutic for treatment of type 2 diabetes. Technological innovation is the application of tripeptide as an oral dosage form to treat human diseases. In our phase I study, we found that DT-110 activates G protein coupled receptor D (MrgprD) signaling pathway that has not been reported to be linked to metabolic diseases. Since activation of MrgprD has been shown to play a protective role in cardiovascular system, our results suggest that DT-110 may have beneficial effects on cardiovascular system in addition to controlling blood glucose levels, and therefore, potentially be a first anti-diabetic drug that can minimize the risk of cardiovascular diseases associated with type 2 diabetes. The long-term goal of this SBIR is to complete the preclinical study on DT-110, file IND, and commercialize it as a new class of anti-type 2 diabetes drugs capable of reducing the risk of cardiovascular diseases associated with type 2 diabetes. The mechanism of action of DT-110 is different from that of the currently available medications for type 2 diabetes. In the Phase II study, we will test the hypothesis that DT-110 specifically acts on this novel signaling pathway to effectively lower the blood glucose levels and protecting cardiovascular system in the patients with type 2 diabetes. Specific aims of this Phase II SBIR are 1) to examine the therapeutic roles of DT-110 in controlling glucose levels and in regulation of blood vessel vasodilation in the genetically modified mice, 2) to develop an enteric coated DT-110, and 3) to determine the blood glucose lowering effect of DT-110 in a large animal model. This study will provide significant information for our understanding of novel mechanism of action of DT-110 and its efficacy in various animal models to support IND filing, and ultimately lead to successful development of a new drug for treatment of type 2 diabetes, which may also has a protective effect on cardiovascular system.