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

• 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
• 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

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.

项目总结/摘要 糖尿病是一个日益严重的全球性健康问题。在胰岛素发现后的100年里， 在糖尿病患者的护理方面，包括长效胰岛素制剂， 胰岛素泵、连续葡萄糖监测仪和影响胰岛素的多种药理学试剂 分泌和敏感性。尽管有这些进展，但大多数糖尿病患者目前仍不能达到 推荐的血糖控制目标。虽然糖尿病患者移植供体来源的 胰岛或完整的胰腺仍然是一种罕见的程序，由于有限的来源材料，这些细胞为基础的 治疗在恢复血糖控制方面非常有效。为了使基于细胞的治疗， 为了使更多的糖尿病患者能够获得治疗，再生医疗解决方案（RMS）开发了一种专有方案， 用于将诱导多能干细胞（iPSC）（一种几乎无限的细胞来源）转化为胰岛样细胞簇， 包括产生胰岛素的β-样细胞的细胞。这些细胞表现出类似于初级β 细胞在体外和移植到糖尿病小鼠后，表明它们作为基于细胞的治疗的潜力 治疗糖尿病然而，与所有基于iPSC的疗法一样，安全性问题仍然存在：即使是移植一个 基于iPSC的产品中少量增殖细胞可导致不期望的副产物或肿瘤 在移植部位形成。为了解决这一潜在风险，植入治疗公司开发了一种新的基因治疗方法， 修饰的iPSC系，FailSafeTM，其中胸苷激酶基因同源整合在 细胞周期调控基因CDK 1。用FDA批准的药物治疗FailSafeTM细胞 因此更昔洛韦导致选择性消除活跃增殖的细胞。在这个项目中，我们将联合收割机 FailSafeTM iPSC和RMS的专有协议，用于生产胰岛样细胞簇，以证明 该组合产品产生更安全的基于细胞的糖尿病治疗的潜力。首先，我们将定义 最佳条件消融增殖细胞从胰岛样集群在文化。接下来，我们将演示 在糖尿病小鼠模型中治疗的FailSafeTM簇的安全性和有效性。所有这些 实验将为开发基于细胞的糖尿病治疗奠定基础， 与竞争产品相比的安全性。