Human Induced Pluripotent Stem Cell-Derived Beta-Cells for Drug and Toxicity Testing

用于药物和毒性测试的人类诱导多能干细胞衍生的β细胞

• 批准号: 8834007
• 负责人: Erik J Forsberg
• 金额: $ 22.2万
• 依托单位: REGENERATIVE MEDICAL SOLUTIONS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-18 至 2015-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8834007
• 关键词: Address; American; Animals; Beta Cell; Biological Assay; Cell Differentiation process; Cell Line; Cell Therapy; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Client; Commit; Cryopreservation; Data; Databases; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Drug Formulations; Drug toxicity; Effectiveness; Endoderm; Epigenetic Process; European; Evaluation; Exhibits; Flow Cytometry; Gene Mutation; Genetic; Glucagon; Glucose; Goals; Government; Grant; Growth; Growth Factor; Health; Hormonal; Human; Immunofluorescence Microscopy; In Vitro; Insulin; International; Market Research; Marketing; Measurable; Medical; Methods; Mono-S; Mus; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pancreas; Pathway interactions; Patients; Persons; Pharmacologic Substance; Phase; Pluripotent Stem Cells; Population; Process; Production; Protocols documentation; Quality Control; Research; Reverse Transcriptase Polymerase Chain Reaction; Solutions; Source; Staging; Stem cells; Techniques; Testing; Therapeutic; Tissue Model; Toxic effect; Toxicity Tests; Transplantation; Treatment Efficacy; Variant; Work; base; cell type; commercialization; cost; diabetic; drug discovery; drug testing; efficacy testing; human embryonic stem cell; human embryonic stem cell line; improved; indexing; induced pluripotent stem cell; insulin secretion; islet; meetings; novel; phase 1 study; preclinical efficacy; preclinical toxicity; progenitor; public health relevance; regenerative; research and development; scale up

 DESCRIPTION (provided by applicant): Diabetes represents one of the most serious health crises worldwide. It is estimated by the American Diabetes Association that one person is diagnosed with diabetes every 17 seconds, while the International Diabetes Federation states that one person dies every seven seconds from diabetes. Diabetes growth continues to skyrocket, with over 382 million cases worldwide, and according to the Centers of Disease Control, one out of every three Americans will have Type II diabetes by 2050. Replacement of deficient β cells with human islets has proven successful in treating diabetes. Unfortunately, the high cost, unpredictable availability, and variable quality of human islets hinder wide spread application. Thus, an abundant supply of high-quality β-like cells generated from human pluripotent stem cells (hPSCs) has tremendous implications for both therapeutic application and the development of drug discovery platforms. RMS has developed and marketed a novel in vitro differentiation kit (ProgenMix(r)) that combines a precise, stepwise combination of growth factors, to generate β-like cells from hPSCs. RMS has been working with multiple major pharmaceutical companies, who have tried ProgenMix(r) to differentiate human induced pluripotent stem cells (hiPSCs) into pancreatic cells for use in drug discovery, toxicity and efficacy studies. One company concluded that the resultant cells are mature enough to conduct a mouse study to reverse diabetes in mice, a strong indication of the potential usefulness of pancreatic cells grown with RMS' techniques. Beyond their potential use in transplantation to treat diabetes, human β cells are needed to test candidate therapies for efficacy and toxicity. The development of candidate therapies requires extensive preclinical efficacy and toxicity testing but traditional animal and cadaveric tissue models have been inadequate. The recent introduction of human induced pluripotent stem cell (hPSC)-derived differentiated cells for testing candidate compounds in preclinical efficacy and toxicity studies has led to the commercial availability of several differentiated human cell types. However, the conspicuous absence of a β cell product remains as a significant barrier to determining whether candidate therapies exhibit β cell toxicity or promote β cell function. Hence, RMS' ProgenMix(r) protocol represents a significant advancement towards the use of β cells in routine toxicity and efficacy testing of candidate therapies. This proposal will focus on testing 10 hiPSC lines for their abilit to differentiate into functional β-like cells that exhibit significant glucose stimulated insulin secretion (GSIS). We expect to identify 3-5 hiPSC lines that repeatedly meet or exceed our release specifications for a β-like cell product which will be made available to our customers for internal toxicity and efficacy testing. Thus, an outcome of the project will be a database or compendium of phenotypic and functional data related to the variability of pancreatic lineage and β-like cell differentiation from a variety of hiPSCs. The hiPSCs selected for the proposed studies will be only those that have a clear commercialization pathway allowing RMS to distribute β-like cells to commercial and non-commercial organizations.

 描述(申请人提供)：糖尿病是全球最严重的健康危机之一。据美国糖尿病协会估计，每17秒就有一人被诊断为糖尿病，而国际糖尿病联合会表示，每七秒就有一人死于糖尿病。糖尿病的增长继续飙升，全球有超过3.82亿例糖尿病病例，根据疾病控制中心的数据，到2050年，每三个美国人中就有一个会患有II型糖尿病。用人类胰岛替换缺陷的β细胞已被证明在治疗糖尿病方面取得了成功。不幸的是， 人类胰岛的高成本、不可预测的可用性和可变的质量阻碍了广泛的应用。因此，从人类多能干细胞(HPSC)中获得高质量的β样细胞对于治疗应用和药物发现平台的开发都具有巨大的意义。RMS已经开发并销售了一种新型的体外分化试剂盒(ProgenMix(R))，该试剂盒结合了精确、循序渐进的生长因子组合，可以从hPSC生成β样细胞。RMS一直在与多家主要制药公司合作，这些公司已经尝试使用ProgenMix(R)将人类诱导多能干细胞(HiPSCs)分化为胰腺细胞，用于药物发现、毒性和疗效研究。一家公司得出结论，合成的细胞足够成熟，可以在小鼠身上进行逆转糖尿病的小鼠研究，这有力地表明了用RMS技术培养的胰腺细胞的潜在用处。除了用于移植治疗糖尿病的潜在用途外，还需要人类β细胞来测试候选疗法的有效性和毒性。候选疗法的开发需要广泛的临床前疗效和毒性测试，但传统的动物和身体组织模型已经不够。最近引入了人类诱导多能干细胞(HPSC)来源的分化细胞，用于在临床前疗效和毒性研究中测试候选化合物，从而导致了几种分化的人类细胞类型的商业应用。然而，明显缺乏β细胞产品仍然是确定候选疗法是否表现出β细胞毒性或促进β细胞功能的一个重要障碍。因此，RMS的ProgenMix(R)协议代表着在候选疗法的常规毒性和有效性测试中使用β细胞的重大进步。这项建议将集中在测试10个HIPSC株分化为具有功能的β样细胞的能力，这些细胞表现出显著的葡萄糖刺激的胰岛素分泌(GSI)。我们预计将确定3-5个HIPSC品系，这些品系反复达到或超过我们对类β细胞产品的发布规格，将提供给我们的客户用于 体内毒性和药效试验。因此，该项目的一个结果将是建立一个数据库或概要，其中包括与各种HPSC的胰腺谱系和β样细胞分化的可变性相关的表型和功能数据。为拟议的研究选择的β将只是那些具有明确的商业化途径的HIPSC，允许RMS向商业和非商业组织分发HPSC样细胞。

项目成果

Intracameral Microimaging of Maturation of Human iPSC Derivatives into Islet Endocrine Cells.

• DOI: 10.1177/09636897211066508
• 发表时间: 2022-01
• 期刊: Cell transplantation
• 影响因子: 3.3
• 作者: Zhao K;Shi Y;Yu J;Yu L;Mael A;Li Y;Kolton A;Joyce T;Odorico J;Berggren PO;Yang SN
• 通讯作者: Yang SN