Biomarkers and Precision Therapy for Primary Immunodeficiencies: An In Vitro Study Based on Induced Pluripotent Stem Cells From Patients

Clin Pharmacol Ther. 2020 Aug;108(2):358-367. doi: 10.1002/cpt.1837. Epub 2020 May 9.


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 and 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 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide 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 a low dose of mepacrine and higher expression of cyclic guanosine monophosphate-adenosine monophosphate synthase, 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 that is useful to investigate the mechanisms of drugs potentially effective in AT and AGS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia / drug therapy*
  • Ataxia Telangiectasia / genetics
  • Ataxia Telangiectasia / immunology
  • Ataxia Telangiectasia / metabolism
  • Autoimmune Diseases of the Nervous System / drug therapy*
  • Autoimmune Diseases of the Nervous System / genetics
  • Autoimmune Diseases of the Nervous System / immunology
  • Autoimmune Diseases of the Nervous System / metabolism
  • Biomarkers / metabolism
  • Cell Line
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Clinical Decision-Making
  • Dexamethasone / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Resistance
  • Genetic Predisposition to Disease
  • Humans
  • Immunologic Factors / pharmacology*
  • Induced Pluripotent Stem Cells / drug effects*
  • Induced Pluripotent Stem Cells / immunology
  • Induced Pluripotent Stem Cells / metabolism
  • Lenalidomide / pharmacology
  • Mercaptopurine / pharmacology
  • Nervous System Malformations / drug therapy*
  • Nervous System Malformations / genetics
  • Nervous System Malformations / immunology
  • Nervous System Malformations / metabolism
  • Phenotype
  • Precision Medicine*
  • Predictive Value of Tests
  • Quinacrine / pharmacology
  • Thalidomide / pharmacology
  • Thioguanine / pharmacology


  • Biomarkers
  • Immunologic Factors
  • Thalidomide
  • Dexamethasone
  • Mercaptopurine
  • Lenalidomide
  • Thioguanine
  • Quinacrine

Supplementary concepts

  • Aicardi-Goutieres syndrome