Development of a safer stem cell-based diabetes therapy via suicide gene-mediated ablation of proliferative cells

通过自杀基因介导的增殖细胞消融开发更安全的基于干细胞的糖尿病疗法

基本信息

批准号：
10482646
负责人：
DENA E COHEN
金额：
$ 25.96万
依托单位：
REGENERATIVE MEDICAL SOLUTIONS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10482646
关键词：
Ablation Address Alleles Animals Beta Cell Biological Assay Blood Glucose C-Peptide CDC2 gene Cadaver Caring Cell Cycle Cell Differentiation process Cell Line Cell Proliferation Cell Survival Cell Therapy Cell Transplantation Cells Development Diabetes Mellitus Diabetic mouse Dose Drug Implants Endocrine FDA approved Fibrous capsule of kidney Formulation Foundations Ganciclovir Generations Genetic Glucose Glucose tolerance test Health Human Immunocompromised Host Immunosuppression In Vitro Insulin Insulin Infusion Systems Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Lead Long-Acting Insulin Mediating Medical Mitotic Modeling Modification Monitor Mus Organ Donor Pancreas Pancreas Transplantation Patients Pharmaceutical Preparations Pharmacology Population Preparation Procedures Production Proliferating Protocols documentation Rattus Regulator Genes Residual state Risk Safety Site Source Stem cell transplant System TK Gene Technology Testing Therapeutic Tissues Transplantation Undifferentiated base blood glucose regulation cell type cost diabetes mellitus therapy diabetic patient differentiation protocol experimental study glucose monitor glycemic control graft function humanized mouse immunogenicity improved in vivo in vivo evaluation induced pluripotent stem cell insulin secretion insulin sensitivity islet mouse model new technology novel phase 2 study post-transplant regenerative safety study stem cell therapy stem cells suicide gene tissue stem cells tool tumor tumorigenic virtual

项目摘要

Project Summary/Abstract Diabetes is an increasingly important health problem worldwide. In the 100 years since the discovery of insulin, tremendous advances have been made in the care of diabetic patients, including long-acting insulin formulations, insulin pumps, continuous glucose monitors, and wide array of pharmacologic agents that influence insulin secretion and sensitivity. Despite all of these advances, a majority of diabetic patients cannot achieve currently recommended targets for blood glucose control. Although transplantation of diabetic patients with donor-derived pancreatic islets or intact pancreas remains a rare procedure due to limited source material, these cell-based therapies are extremely effective in restoring blood glucose control. In order to make a cell-based therapy for diabetes available to more patients, Regenerative Medical Solutions (RMS) has developed a proprietary protocol for converting induced pluripotent stem cells (iPSC), a virtually unlimited cell source, into islet-like clusters of cells that include insulin-producing beta-like cells. These cells demonstrate functionality similar to primary beta cells both in vitro and after transplantation into diabetic mice, indicating their potential as a cell-based therapy for diabetes. However, as will all iPSC-based therapies, safety concerns remain: the transplantation of even a small number of proliferative cells in an iPSC-based product may result in undesired outgrowths or tumor formation at the graft site. To address this potential risk, Implant Therapeutics has developed a novel genetically modified iPSC line, FailSafeTM, in which the thymidine kinase gene is homozygously integrated downstream of the essential cell cycle regulatory gene CDK1. Treatment of FailSafeTM cells with the FDA-approved drug ganciclovir thus leads to selective elimination of actively proliferating cells. In this project, we will combine FailSafeTM iPSC and RMS’s proprietary protocol for the production of islet-like clusters of cells to demonstrate the potential of the combined product to produce a safer cell-based therapy for diabetes. First, we will define optimal conditions for the ablation of proliferating cells from islet-like clusters in culture. Next, we will demonstrate the safety and efficacy of the treated FailSafeTM clusters in a mouse model of diabetes. Together, these experiments will lay the foundation for the development of a cell-based therapy for diabetes with an improved safety profile compared to competing products.

项目概要/摘要自胰岛素发现以来的 100 年来，糖尿病已成为全球日益重要的健康问题。在糖尿病患者的护理方面取得了巨大进步，包括长效胰岛素制剂，胰岛素泵、连续血糖监测仪以及影响胰岛素的多种药物尽管取得了所有这些进展，但大多数糖尿病患者目前仍无法实现。推荐的血糖控制目标虽然是糖尿病患者的移植来源。由于来源有限，胰岛或完整胰腺仍然是一种罕见的手术，这些基于细胞的治疗对于恢复血糖控制非常有效，以进行基于细胞的治疗。再生医疗解决方案 (RMS) 开发了专有方案用于将几乎无限的细胞来源诱导多能干细胞 (iPSC) 转化为胰岛样细胞簇包括产生胰岛素的β样细胞这些细胞表现出与初级β类似的功能。细胞在体外和移植到糖尿病小鼠后，表明它们作为细胞疗法的潜力然而，与所有基于 iPSC 的疗法一样，安全问题仍然存在：即使是移植。基于 iPSC 的产品中的少量增殖细胞可能会导致不良的生长或肿瘤为了解决这种潜在风险，Implant Therapeutics 开发了一种新型基因疗法。改良的 iPSC 系 FailSafeTM，其中胸苷激酶基因纯合地整合在使用 FDA 批准的药物治疗 FailSafeTM 细胞的必需细胞周期调节基因 CDK1。因此，更昔洛韦会选择性地消除活跃增殖的细胞，在这个项目中，我们将结合起来。 FailSafeTM iPSC 和 RMS 用于生产胰岛样细胞簇的专有协议进行演示组合产品产生更安全的基于细胞的糖尿病疗法的潜力首先，我们将定义。接下来，我们将演示从培养物中的胰岛样簇中消融增殖细胞的最佳条件。治疗后的 FailSafeTM 簇在糖尿病小鼠模型中的安全性和有效性。实验将为开发基于细胞的糖尿病疗法奠定基础，该疗法具有改进的效果与竞争产品相比的安全性。