TY - JOUR
T1 - Biomarkers and precision therapy for primary immunodeficiencies
T2 - an in vitro study based on induced pluripotent stem cells (iPSCs) from patients
AU - Genova, Elena
AU - Cavion, Federica
AU - Lucafò, Marianna
AU - Pelin, Marco
AU - Lanzi, Gaetana
AU - Masneri, Stefania
AU - Ferraro, Rosalba Monica
AU - Fazzi, Elisa Maria
AU - Orcesi, Simona
AU - Decorti, Giuliana
AU - Tommasini, Alberto
AU - Giliani, Silvia
AU - Stocco, Gabriele
N1 - This article is protected by copyright. All rights reserved.
PY - 2020/4/3
Y1 - 2020/4/3
N2 - 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.
AB - 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.
U2 - 10.1002/cpt.1837
DO - 10.1002/cpt.1837
M3 - Article
C2 - 32243572
VL - 108
SP - 358
EP - 367
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
SN - 0009-9236
IS - 2
ER -