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 当身体对胰岛素的需求超过胰腺β细胞产生胰岛素的能力时，就会出现糖尿病 然后把它藏起来。这可能是由于自身免疫破坏β细胞(I型糖尿病)引起的，这是一种 胰岛素抵抗和随后的β细胞衰竭(II型糖尿病)，或损害β细胞的原发基因缺陷 发育和功能，包括成熟期发作性青年糖尿病(MODY)和Wolfram综合征 (Ws)。截至2012年，约有2910万美国人患有糖尿病，导致直接医疗 费用为1,760亿美元(《国家糖尿病统计报告，2014》)。为了满足这种日益增长的需求 患者群体，伊利百合、阿斯利康和诺和诺德等顶级制药公司积极 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，药物发现 由于缺乏一个β细胞药物筛选平台来捕获这两种药物，这一领域的努力受到了阻碍 患者遗传学和原代β细胞的复杂表型。为了满足这一需求，再生医疗 解决方案公司(RMS)率先采用了一种简单的专有协议来生成类胰岛群集(ILC)，其中包含 多种类型的胰腺内分泌细胞，包括产生胰岛素的β样细胞 多能干细胞(IPSC)。RMS已经证明，当这些ILC来自健康的捐赠者IPSC时， 捕获原代β细胞的许多复杂表型，包括关键标记基因和 强健的葡萄糖刺激胰岛素分泌。为了展示该平台对检测病毒的效用 与特定患者基因型相关的病理，RMS将从患有β的MODY患者中产生类似于RMS的细胞 葡萄糖激酶(GCK)基因和WS患者特征明确的突变，由基因突变引起 Wolframin基因(WSF1)。携带这些突变的ILC复制已建立的缺陷的能力 在β中，将展示在患者中看到的细胞功能，并将制造出初始数量的细胞 可供RMS的现有客户使用。在一项后续的第二阶段提案中，来自更多患者的β样细胞 复杂遗传学(即I型和II型糖尿病)将被开发用于高通量筛查 药物发现的平台。