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

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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.