Biomarkers and precision therapy for primary immunodeficiencies: an in vitro study based on induced pluripotent stem cells (iPSCs) from patients.

Ataxia Telangiectasia (AT) and Aicardi Goutières syndrome (AGS) are inherited disorders of immunity with prevalent neurological phenotype. Available treatments are only partially effective and the prognosis is poor. Induced pluripotent stem cells (iPSCs) are obtained by reprogramming patient somatic cells preserving the donor individual genetic heritage and creating patient specific disease models, useful to investigate pathogenesis, drug effects and to develop precision therapies. The aim is to investigate the cytotoxicity of a panel of immunomodulators using iPSCs of patients with AT or different forms of AGS (AGS1, AGS2 and AGS7). iPSCs were obtained by reprogramming AT and AGS patients' cells and, as a control, the BJ normal human fibroblast line, using Sendai virus. Cytotoxic effects of two drugs proposed to treat respectively AT and AGS (dexamethasone and mepacrine) were tested by the MTT assay after 72 hours exposure. Data were obtained also for other immunomodulatory drugs (thioguanine, mercaptopurine, thalidomide and lenalidomide). Relative expression of genes involved in the tested drug pathways was analyzed. AGS7-derived iPSCs displayed altered viability when treated with low dose of mepacrine, and higher expression of cyclic GMP-AMP synthase (cGAS), which is the main target for mepacrine action. AGS7-derived iPSCs were also more sensitive to thioguanine, while AGS2 and AT iPSCs were less sensitive to this medication than the BJ-iPSC. All iPSCs were equally sensitive to mercaptopurine and resistant to dexamethasone, thalidomide and lenalidomide. This work establishes an innovative in vitro model useful to investigate the mechanisms of drugs potentially effective in AT and AGS.