Preclinical characterization of THR-123 to induce pancreatic beta cell regeneration (Phase I)

THR-123 诱导胰腺 β 细胞再生的临床前表征（第一阶段）

• 批准号: 9465072
• 负责人: Juan Dominguez-Bendala
• 金额: $ 22.39万
• 依托单位: OPHYSIO, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9465072
• 关键词: Academia; Administrator; Adsorption; Agonist; Alloxan; Alpha Cell; B-Lymphocytes; BMP7 gene; Beta Cell; Biotechnology; Cell Therapy; Cells; Clinical; Collaborations; Complement; Cyclic Peptides; Data; Dependence; Development; Diabetes Mellitus; Diabetic mouse; Dose; Drug Kinetics; Duct (organ) structure; Ductal; Ectopic Expression; Endocrine; Excretory function; Family member; Generations; Goals; Human; Hyperglycemia; Immunofluorescence Immunologic; In Situ; In Vitro; Industry; Injection of therapeutic agent; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Investigational New Drug Application; Islets of Langerhans; Islets of Langerhans Transplantation; Knowledge; Lead; Leadership; Letters; Link; Mediating; Metabolism; Mission; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pharmaceutical Preparations; Pharmacology; Phase; Process; Proteins; Public Health; Publishing; Regimen; Reporting; Research; Research Institute; Rodent; Saline; Slice; Speed; Stem cells; Structure; Structure of beta Cell of islet; Testing; Therapeutic; Time; Time Study; Tissue Model; Tissues; Toxic effect; Transforming Growth Factor alpha; Transforming Growth Factor beta; Transplantation; United States Food and Drug Administration; Universities; Validation; Washington; analytical tool; animal tissue; clinical application; clinical candidate; clinical development; clinical translation; design; diabetes mellitus therapy; effective therapy; experience; glycemic control; human tissue; in vivo; in vivo Model; interest; islet; mouse model; multidisciplinary; non-genetic; novel; peptidomimetics; pre-clinical; preclinical evaluation; progenitor; receptor; restoration; small molecule; success

The exocrine (acinar/ductal) compartment of the pancreas has been hypothesized to harbor progenitor cells with the ability to give rise to new b-cells. The activation of such progenitors may potentially result in new b-cell formation through differentiation, rather than reprogramming. We hypothesized that, if pancreatic progenitors existed, they would respond to bone morphogenetic protein 7 (BMP-7), a TGF-b family member with dual TGF-b inhibition and BMP stimulation abilities. This hypothesis was premised on the widely reported link between these two concerted actions and expansion of progenitor pools in multiple tissues. Our University of Miami/Diabetes Research Institute (UM/DRI) partners have now reported that BMP-7 mediates the in vitro conversion of human non-endocrine pancreatic tissue into endocrine cells that are functional both in vitro and in vivo. This process entails the activation of progenitor-like cells that co-express PDX1 and ALK3, a BMP-7 receptor. Furthermore, we have confirmed that: (1) THR-123 (an ALK3 agonist cyclic peptide with BMP-7-like activity) can induce the same effect; and (2) ALK3+/Pdx1+ cells are also present in the mouse pancreas, which affords us the possibility of testing the feasibility of endogenous regeneration in a setting not involving transplantation. Preliminary data indicate that a daily regimen of THR-123 injections administered to alloxan-treated diabetic mice drastically reduces hyperglycemia vs. saline-treated controls. Immunofluorescence analyses of treated mice show small islet-like structures with highly increased proliferation rates, which are largely absent from saline-treated controls. Our results are consistent with the hypothesis that THR-123 stimulates the generation of new islets from progenitor-like cells –a hypothesis that our UM/DRI associates are fully dissecting in the context of a parallel project. Regardless of the mechanism of action, the observed action of THR-123 on b-cell formation and enhanced glycemic control warrants the conduct of a project focused on the validation of this small molecule as a therapeutic lead for the induction of b-cell regeneration in animal and human tissue models. Thus, the general objective of this Phase I proposal is to confirm the suitability of THR- 123 for clinical development, with a single specific aim (Confirmation of THR-123-induced b-cell regeneration in diabetic mice and live human pancreatic slices). In short, we will conduct dose-dependence and time-course studies to confirm our preliminary observations on b-cell neogenesis in murine models in vivo as well as in cultured human pancreatic slices –a novel analytical tool developed as a collaboration between the Diabetes Research Institute (DRI) and nPOD (Network of Pancreatic Donors with Diabetes) that allows for the real-time study of the regeneration of b-cells within their intact pancreatic niche. If successful, these studies will seamlessly transition to a Phase II proposal aimed at conducting a full preclinical ADME-Tox (adsorption, distribution, metabolism, excretion and toxicity) and pharmacokinetic (PK) profile of THR-123 with the goal of submitting an investigational new drug (IND) application to the Food and Drug Administration (FDA). The demonstration that resident progenitor-like cells within the pancreas can be activated in situ through a simple non-genetic intervention could open the door to the design of potentially transformative therapies for diabetes.

胰腺的外分泌区(腺泡/导管)被假定为藏匿祖细胞。 有能力产生新的b细胞的细胞。这些祖细胞的激活可能会导致新的 B细胞是通过分化形成的，而不是重新编程。我们假设，如果胰腺 祖细胞存在，它们会对骨形态发生蛋白7(BMP-7)产生反应，骨形态发生蛋白7是转化生长因子-b家族成员 具有双重的转化生长因子-β抑制和骨形态发生蛋白刺激能力。这一假设的前提是广泛报道的 这两个协同作用和多个组织中祖细胞池的扩大之间的联系。我们的大学 迈阿密/糖尿病研究所(UM/DRI)的合作伙伴现在报告了BMP-7在体外介导 人非内分泌胰腺组织在体外和体外转化为具有功能的内分泌细胞 在活体内。这个过程需要激活共表达PDX1和ALK3的祖细胞样细胞，ALK3是一种BMP-7 受体。此外，我们还证实：(1)Thr-123(一种与BMP-7类似的ALK3激动型环肽 活性)可以诱导同样的效应；以及(2)ALK3+/Pdx1+细胞也存在于小鼠胰腺中，这 使我们有可能在不涉及的情况下测试内源性再生的可行性 移植。初步数据显示，每天给四氧嘧啶治疗的患者注射Thr-123的方案 与盐水治疗的对照组相比，糖尿病小鼠显著降低了高血糖。免疫荧光分析 经处理的小鼠表现出小的胰岛样结构，其增殖率大大增加，但基本上不存在。 来自生理盐水处理的对照组。我们的结果与Thr-123刺激血管紧张素转换酶的假设一致 从祖细胞样细胞生成新的胰岛--这是一个假设，即我们的UM/DRI相关性完全 在并行项目的背景下进行剖析。无论作用机制如何，观察到的 关于b细胞形成和增强血糖控制的Thr-123保证了一个项目的开展，该项目的重点是 验证这种小分子作为治疗先导诱导动物和小鼠B细胞再生 人体组织模型。因此，本第一阶段提案的总体目标是确认THR的适宜性- 123用于临床开发，只有一个特定目标(确认Thr-123诱导的b细胞再生 在糖尿病小鼠和活体人胰腺切片中)。简而言之，我们将进行剂量依赖和时间过程 研究证实我们在小鼠体内模型中以及在小鼠体内的b细胞新生的初步观察 培养的人胰腺切片--一种新的分析工具，用于糖尿病患者之间的合作 研究机构(DRI)和糖尿病胰腺捐赠者网络(NPOD)，允许实时 B细胞在其完整的胰脏壁龛内再生的研究。如果成功，这些研究将 无缝过渡到旨在进行完整的临床前ADME-Tox(吸附， Thr-123的分布、代谢、排泄和毒性)和药代动力学(PK)谱，目的是 向食品和药物管理局(FDA)提交研究用新药(IND)申请。 证明胰腺内的常驻祖细胞样细胞可以通过一种 简单的非遗传干预可能会为设计潜在的变革性治疗方法打开大门 糖尿病。