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（腺泡/导管）隔室已被认为是港口祖先 具有产生新B细胞的能力。这种祖细胞的激活可能会导致新的 通过分化而不是重新编程的B细胞形成。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）响应，TGF-B家族成员 具有双重TGF-B抑制和BMP刺激能力。该假设以广泛报道的 在这两个协同的动作与祖细胞池的扩展多次之间联系。我们的大学 迈阿密/糖尿病研究所（UM/DRI）合作伙伴现已报道BMP-7介导了体外 人类非内分泌胰腺组织转化为体外功能和功能性的内分泌细胞 体内。这个过程需要激活祖细胞的激活，该细胞共表达PDX1和ALK3，BMP-7 接收者。此外，我们已经确认：（1）Thr-123（具有BMP-7样的Alk3激动剂环状肽 活动）可以诱导相同的效果； （2）ALK3+/PDX1+细胞也存在于小鼠胰腺中，其中 为我们提供了在不涉及的环境中测试内源性再生可行性的可能性 移植。初步数据，表明每天的THR-123注射疗法给予了对Alloxan处理的 糖尿病小鼠大大降低了高血糖与盐水处理的对照。免疫荧光分析 处理的小鼠显示出小胰岛状结构，增殖率高度增加，这在很大程度上没有 来自盐水处理的对照。我们的结果与THR-123刺激的假设一致 从祖细胞样细胞中产生的新胰岛 - 我们的UM/DRI员工是完全的假设 在平行项目的上下文中解剖。无论作用机理如何，观察到的动作 在B细胞形成和增强血糖控制的THR-123值得进行的项目集中于该项目 验证该小分子是诱导动物B细胞再生的治疗铅 人体组织模型。这是I阶段提案的一般目标是确认该问题的适用性 123用于临床开发，具有单一特定的目的（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间顺序 研究确认我们对体内鼠模型中B细胞新作用的初步观察 培养的人类胰腺切片 - 一种新颖的分析工具，作为糖尿病之间的合作开发 研究机构（DRI）和NPOD（胰腺供体网络与糖尿病的网络），可实时实时 研究B细胞在其完整的胰腺位中的再生。如果成功，这些研究将 无缝过渡到旨在进行完整临床前的TOX的II期建议（吸附， THR-123的分布，新陈代谢，排泄和毒性）和药代动力学（PK）特征 向食品药品监督管理局（FDA）提交投资新药（IND）。 胰腺内常驻祖细胞样细胞的演示可以通过A进行激活 简单的非遗传干预可以打开设计潜在变革性疗法的大门 糖尿病。