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）

基本信息

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
项目类别：
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

项目摘要

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（腺泡/导管）室已被重新捕获以容纳祖细胞具有产生新b细胞能力的细胞此类祖细胞的激活可能会产生新的b细胞。我们再次认识到，如果胰腺细胞通过分化形成，而不是重新编程。如果祖细胞存在，它们会对骨形态发生蛋白 7 (BMP-7)（TGF-b 家族成员）做出反应具有双重抑制 TGF-b 和刺激 BMP 的能力，这一假设是基于广泛报道的。这两个协同行动与我们大学多个组织中祖细胞库的扩展之间的联系。迈阿密/糖尿病研究所 (UM/DRI) 合作伙伴现已报告，BMP-7 介导体外将人类非内分泌胰腺组织转化为在体外和体外均具有功能的内分泌细胞该过程需要激活共表达 PDX1 和 ALK3（一种 BMP-7）的类祖细胞。此外，我们还证实：（1）THR-123（一种具有BMP-7样功能的ALK3激动剂环肽）。 (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环境中测试内源再生的可行性初步数据表明，每日注射 THR-123 方案给予四氧嘧啶治疗。与盐水处理的对照组相比，糖尿病小鼠的高血糖显着降低。小鼠表现出经过处理的小胰岛样结构，其增殖率大大增加，而这种结构基本上不存在我们的结果与 THR-123 刺激的假设一致。从类祖细胞中产生新的胰岛——我们的 UM/DRI 同事们的假设是完全无论作用机制如何，都要在并行项目的背景下进行剖析。 THR-123 对 b 细胞形成和增强血糖控制的影响值得开展一个专注于验证该小分子作为诱导动物 B 细胞再生的治疗先导药物因此，第一阶段提案的总体目标是确认 THR- 的适用性。 123用于临床开发，具有单一的具体目标（确认THR-123诱导的b细胞再生简而言之，我们将进行剂量依赖性和时程研究。研究证实了我们对小鼠模型体内和体内 b 细胞新生的初步观察培养的人类胰腺切片——糖尿病与糖尿病研究中心合作开发的一种新型分析工具研究所 (DRI) 和 nPOD（糖尿病胰腺捐献者网络）可实现实时研究完整胰腺生态位内的 B 细胞再生如果成功，这些研究将无缝过渡到旨在进行全面临床前 ADME-Tox（吸附、 THR-123 的分布、代谢、排泄和毒性）和药代动力学 (PK) 概况，目标是向食品和药物管理局（FDA）提交研究性新药（IND）申请。证明胰腺内的驻留类祖细胞可以通过简单的非基因干预可以为设计潜在的变革性疗法打开大门糖尿病。