Biomarkers and Precision Therapy for Primary Immunodeficiencies: An In Vitro Study Based on Induced Pluripotent Stem Cells From Patients.
Ataxia Telangiectasia
/ drug therapy
Autoimmune Diseases of the Nervous System
/ drug therapy
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
Lenalidomide
/ pharmacology
Mercaptopurine
/ pharmacology
Nervous System Malformations
/ drug therapy
Phenotype
Precision Medicine
Predictive Value of Tests
Quinacrine
/ pharmacology
Thalidomide
/ pharmacology
Thioguanine
/ pharmacology
Journal
Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
21
11
2019
accepted:
06
03
2020
pubmed:
4
4
2020
medline:
25
5
2021
entrez:
4
4
2020
Statut:
ppublish
Résumé
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.
Substances chimiques
Biomarkers
0
Immunologic Factors
0
Thalidomide
4Z8R6ORS6L
Dexamethasone
7S5I7G3JQL
Mercaptopurine
E7WED276I5
Lenalidomide
F0P408N6V4
Thioguanine
FTK8U1GZNX
Quinacrine
H0C805XYDE
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
358-367Subventions
Organisme : Italian Ministry of Health (IRCCS Burlo Garofolo)
ID : RC 7_2014
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.
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