Diabetes drug screening platforms using patient pancreatic islet-like cells generated from induced pluripotent stem cells

使用诱导多能干细胞产生的患者胰岛样细胞的糖尿病药物筛选平台

• 批准号: 9201699
• 负责人: Erik J Forsberg
• 金额: $ 22.49万
• 依托单位: REGENERATIVE MEDICAL SOLUTIONS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-20 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9201699
• 关键词: American; Autoimmune Process; Benchmarking; Beta Cell; Biological Assay; Cell Line; Cell physiology; Cells; Complex; Detection; Development; Diabetes Mellitus; Disease; Endocrine; Failure; Foundations; Gene Expression; Genes; Genetic; Glucokinase; Glucose; Health; Human; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Lilium; Medical; Medicine; Modeling; Mutation; New York; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Parents; Pathology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Population; Preclinical Drug Evaluation; Production; Protocols documentation; Reporting; Research; Stem cells; Stress; Structure of beta Cell of islet; Testing; United States; WFS1 gene; Wolfram Syndrome; Work; abstracting; base; cell type; cost; drug discovery; drug testing; gene correction; genotyped patients; high throughput screening; induced pluripotent stem cell; insulin secretion; islet; meetings; novel therapeutics; patient population; regenerative; screening; small molecule; statistics; tool; type I and type II diabetes

Project Summary/Abstract Diabetes manifests when the body’s demand for insulin exceeds the capacity of pancreatic β cells to produce and secrete it. This can arise due to autoimmune destruction of β cells (Type I diabetes), a combination of insulin resistance and subsequent β cell failure (Type II diabetes), or primary genetic defects that impair β cell development and function including maturity onset diabetes of the young (MODY) and Wolfram Syndrome (WS). As of 2012, approximately 29.1 million Americans suffered from diabetes, resulting in direct medical costs of $176 billion (National Diabetes Statistics Report, 2014). In order to meet the needs of this growing patient population, top pharmaceutical companies such as Eli Lily, AstraZeneca, and Novo Nordisk have active diabetes pipelines to identify and test molecules that enhance β cell function. Unfortunately, drug discovery efforts in this space are hampered by the absence of a β cell drug screening platform that captures both patient genetics and the complex phenotypes of primary β cells. To meet this need, Regenerative Medical Solutions (RMS) has pioneered a simple proprietary protocol to produce islet-like clusters (ILC) containing multiple pancreatic endocrine cell types, including insulin-producing β-like cells, from human induced pluripotent stem cells (iPSC). RMS has demonstrated that these ILC, when derived from healthy donor iPSC, capture many of the complex phenotypes of primary β cells, including expression of key marker genes and robust glucose stimulated insulin secretion. In order to demonstrate the utility of the platform for detection of pathologies associated with specific patient genotypes, RMS will generate β-like cells from MODY patients with well-characterized mutations in the glucokinase (GCK) gene and patients with WS, caused by mutations in the wolframin gene (WSF1). The ability of ILC harboring these mutations to replicate the well-established deficits in β cell function seen in the patients will be demonstrated, and initial quantities of the cells will be made available to RMS’s existing customers. In a follow-on Phase II proposal, β-like cells from patients with more complex genetics (i.e. Type I and Type II diabetes) will be developed for use as high-throughput screening platforms for drug discovery.

项目摘要/摘要 当人体对胰岛素的需求超过胰腺β细胞产生的能力时，糖尿病就会表现出来 并秘密。这可能是由于自身免疫性破坏β细胞（I型糖尿病），这是 胰岛素抵抗和随后的β细胞衰竭（II型糖尿病）或损害β细胞的主要遗传缺陷 开发和功能，包括年轻（Mody）和Wolfram综合征的成熟糖尿病 （WS）。截至2012年，大约2910万美国人患有糖尿病，导致直接医疗 成本为1760亿美元（国家糖尿病统计报告，2014年）。为了满足这种成长的需求 患者人数，高级制药公司，例如Eli Lily，Astrazeneca和Novo Nordskity活跃 糖尿病管道以识别和测试增强β细胞功能的分子。不幸的是，毒品发现 缺乏捕获两者 患者遗传学和原代β细胞的复杂表型。为了满足这种需求，再生医学 解决方案（RMS）启动了一个简单的专有协议，以生产包含胰岛状簇（ILC） 来自人类诱导的多种胰腺内分泌细胞类型，包括产生胰岛素的β样细胞 多能干细胞（IPSC）。 RMS证明，这些ILC在健康的供体IPSC中得出 捕获原代β细胞的许多复杂表型，包括关键标记基因的表达和 鲁棒的葡萄糖刺激胰岛素分泌。为了证明平台检测的实用性 与特定患者基因型相关的病理学，RMS将产生来自Mody患者的β样细胞 葡萄糖酶（GCK）基因和WS患者的特征性突变，由突变引起 Wolframin基因（WSF1）。 ILC携带这些突变复制良好缺陷的能力 在患者中看到的β细胞功能中，将证明并将其初始数量 RMS的现有客户可用。在随后的II期建议中，来自更多患者的β样细胞 将开发复杂的遗传学（即I型和II型糖尿病）作为高通量筛查 药物发现平台。