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Biomarkers and Precision Therapy for Primary Immunodeficiencies: An In Vitro Study Based on Induced Pluripotent Stem Cells From Patients.
- Source :
-
Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2020 Aug; Vol. 108 (2), pp. 358-367. Date of Electronic Publication: 2020 May 09. - Publication Year :
- 2020
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Abstract
- 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.<br /> (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)
- Subjects :
- Ataxia Telangiectasia genetics
Ataxia Telangiectasia immunology
Ataxia Telangiectasia metabolism
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
Induced Pluripotent Stem Cells immunology
Induced Pluripotent Stem Cells metabolism
Lenalidomide pharmacology
Mercaptopurine pharmacology
Nervous System Malformations genetics
Nervous System Malformations immunology
Nervous System Malformations metabolism
Phenotype
Predictive Value of Tests
Quinacrine pharmacology
Thalidomide pharmacology
Thioguanine pharmacology
Ataxia Telangiectasia drug therapy
Autoimmune Diseases of the Nervous System drug therapy
Immunologic Factors pharmacology
Induced Pluripotent Stem Cells drug effects
Nervous System Malformations drug therapy
Precision Medicine
Subjects
Details
- Language :
- English
- ISSN :
- 1532-6535
- Volume :
- 108
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Clinical pharmacology and therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 32243572
- Full Text :
- https://doi.org/10.1002/cpt.1837