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

项目总结/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， 这可能是由于β细胞的自身免疫性破坏（I型糖尿病）， 胰岛素抵抗和随后的β细胞衰竭（II型糖尿病），或损害β细胞的原发性遗传缺陷 发育和功能，包括青年成熟型糖尿病（MODY）和Wolfram综合征 （WS）。截至2012年，约有2910万美国人患有糖尿病，导致直接医疗费用增加。 费用为1760亿美元（国家糖尿病统计报告，2014年）。为了满足这一日益增长的需求， 患者人群，顶级制药公司，如Eli Lily，AstraZeneca和Novo Nordisk， 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 这一领域的努力受到缺乏β细胞药物筛选平台的阻碍， 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）开创了一种简单的专有协议，以产生胰岛样集群（ILC）， 多种胰腺内分泌细胞类型，包括产生胰岛素的β样细胞，来自人类诱导的 多能干细胞（iPSC）。RMS已经证明，当这些ILC来源于健康供体iPSC时， 捕获原代β细胞的许多复杂表型，包括关键标志物基因的表达， 葡萄糖刺激胰岛素分泌。为了证明该平台用于检测 与特定患者基因型相关的病理，RMS将从MODY患者产生β样细胞， 葡萄糖激酶（GCK）基因突变和WS患者，由葡萄糖激酶（GCK）基因突变引起， 钨蛋白基因（WSF 1）。携带这些突变的ILC复制已确立的缺陷的能力 将证明在患者中观察到的β细胞功能，并将制备细胞的初始量。 提供给RMS的现有客户。在后续的第二阶段建议中，来自患有更多 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。

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.