Reprogramming of fibroblasts to pluripotency- a new tool to study Primary Immunod

描述（由申请人提供）：原发性免疫缺陷（PID）包括超过150种不同的疾病，其特征在于对感染、自身免疫表现和肿瘤的易感性增加。人类PID的研究对于确定控制免疫系统发育和/或功能的关键机制至关重要。目前已经确定了130多个导致人类PID的基因缺陷。此外，同一基因的不同突变往往与不同的表型相关，表明存在非凡的遗传和表型异质性。尽管取得了这一进展，但仍需要在细胞水平上更好地定义几种形式PID的病理生理学，在相同的实验条件下通过分析携带相同基因中不同突变的患者来源细胞的分化潜力和功能来进行基因型-表型相关性研究，并开发临床前模型以探索具有严重预后的PID的新治疗策略。使用动物模型来解决这些目标具有显著的局限性，因为在同一基因中携带不同突变的模型的可用性有限，并且因为人类和其他物种之间的内在差异。 细胞重编程的最新进展，导致从成熟体细胞（例如，成纤维细胞）产生诱导多能干细胞（iPS），现在首次提供了从携带导致PID的基因的各种突变的患者中创建有价值的多能细胞库的可能性。利用来源于在PID引起基因中具有多种突变的患者的成纤维细胞系的大型储存库的可用性，以及我们在产生人iPS细胞方面的专业知识，我们将创建来自具有明确定义的PID的患者的iPS克隆的储存库。我们将表征患者来源的iPS细胞的干细胞特征和多能性，并将使用遗传工具来确认其患者特异性来源。从PID患者中创建iPS细胞库将为科学界提供无限的祖细胞来源，可用于体外分化和基因型-表型相关性研究，以及用于新治疗策略的安全性和有效性的临床前评估。我们预计，使用这种来自PID患者的iPS细胞库将有助于提高对这些疾病的认识和治疗。 公共卫生相关性：原发性免疫缺陷（PID）包括超过150种不同的疾病，其特征在于对感染、自身免疫表现和肿瘤的易感性增加。从PID患者中获得无限来源的干细胞对于提高疾病机制的知识和帮助开发基于纠正基因缺陷的新治疗方法将是重要的。人类成纤维细胞（即培养的皮肤细胞）可以重新编程成为诱导多能细胞（iPS）细胞。利用我们在产生iPS细胞方面的专业知识和来自PID患者的大量成纤维细胞系的可用性，我们打算创建来自PID患者的第一个iPS细胞库。我们预计，使用PID患者的iPS库将有助于科学界提高对这些疾病的认识和治疗。

DESCRIPTION (provided by applicant): Primary immunodeficiencies (PIDs) comprise over 150 different diseases characterized by increased susceptibility to infections, autoimmune manifestations, and tumors. The study of human PID has been essential to identify key mechanisms that govern development and/or function of the immune system. More than 130 gene defects that are responsible for PID in humans have been identified. In addition, different mutations in the same gene have been often associated with distinct phenotypes, indicating the existence of extraordinary genetic and phenotypic heterogeneity. In spite of this progress, there is a need to better define at the cellular level the pathophysiology of several forms of PID, to perform genotype-phenotype correlation studies by analyzing, under the same experimental conditions, the differentiation potential and function of patient-derived cells carrying different mutations in the same gene, and to develop preclinical models to explore novel therapeutic strategies for PID with a severe prognosis. The use of animal models to address these objectives has significant limitations, because of the limited availability of models carrying different mutations in the same gene, and because of intrinsic differences between humans and other species. Recent advances in cell reprogramming, leading to generation of induced pluripotent stem (iPS) cells from mature somatic cells (eg, fibroblasts), now offer for the first time ever the possibility to create a valuable repository of pluripotent cells from patients carrying various mutations in PID-causing genes. Taking advantage of the availability of a large repository of fibroblast cell lines derived from patients with a variety of mutations in PID-causing genes, and of our expertise in the generation of human iPS cells, we will create a repository of iPS clones from patients with well- defined PID. We will characterize the stemness profile and pluripotency of patient-derived iPS cells, and will use genetic tools to confirm their patient-specific origin. Creation of a repository of iPS cells from patients with PID will provide the scientific community with a limitless source of progenitor cells that can be used for in vitro differentiation and genotype-phenotype correlation studies, and for preclinical evaluation of safety and efficacy of novel therapeutic strategies. We anticipate that use of this repository of iPS cells from patients with PID will help improve the knowledge and treatment of these disorders. PUBLIC HEALTH RELEVANCE: Primary immunodeficiencies (PIDs) comprise over 150 different diseases characterized by increased susceptibility to infections, autoimmune manifestations, and tumors. Availability of a limitless source of stem cells from patients with PID would be important to improve the knowledge of the mechanisms of disease and to assist in the development of novel therapeutic approaches based on correction of the gene defect. Human fibroblasts (ie, cultured skin cells) can be reprogrammed to become induced pluripotent cells (iPS) cells. Taking advantage of our expertise in generation of iPS cells and in availability of a large collection of fibroblast cell lines from patients with PID, we intend to create the first repository of iPS cells from patients with PID. We anticipate that use of this repository of iPS from patients with PID will help the scientific community improve the knowledge and treatment of these disorders.