Pharmacological evaluation of drug therapies in Aicardi-Goutières syndrome: insights from patient-derived neural stem cells
Aicardi-Goutières syndrome (AGS) is a rare genetic disorder classified among type I interferonopathies. Current pharmacological management of AGS is symptomatic and supportive, with recent clinical applications of JAK inhibitors (JAKi) and antiretroviral therapies (RTIs). To investigate the effects...
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Frontiers Media S.A.
2025-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1549183/full |
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| author | Stefania Braidotti Rosalba Monica Ferraro Rosalba Monica Ferraro Raffaella Franca Elena Genova Francesco Giambuzzi Andrea Mancini Valentina Marinozzi Letizia Pugnetti Giulia Zudeh Alessandra Tesser Alberto Tommasini Alberto Tommasini Giuliana Decorti Giuliana Decorti Silvia Clara Giliani Silvia Clara Giliani Gabriele Stocco Gabriele Stocco |
| author_facet | Stefania Braidotti Rosalba Monica Ferraro Rosalba Monica Ferraro Raffaella Franca Elena Genova Francesco Giambuzzi Andrea Mancini Valentina Marinozzi Letizia Pugnetti Giulia Zudeh Alessandra Tesser Alberto Tommasini Alberto Tommasini Giuliana Decorti Giuliana Decorti Silvia Clara Giliani Silvia Clara Giliani Gabriele Stocco Gabriele Stocco |
| author_sort | Stefania Braidotti |
| collection | DOAJ |
| description | Aicardi-Goutières syndrome (AGS) is a rare genetic disorder classified among type I interferonopathies. Current pharmacological management of AGS is symptomatic and supportive, with recent clinical applications of JAK inhibitors (JAKi) and antiretroviral therapies (RTIs). To investigate the effects of these therapies, patient-specific induced pluripotent stem cells (iPSCs) were generated by reprogramming fibroblasts from three AGS patients with distinct genetic mutations (AGS1, AGS2, AGS7) and differentiated into neural stem cells (NSCs). iPSCs and NSCs derived from commercial BJ fibroblasts of a healthy donor served as control. The cytotoxic effects of glucocorticoids, thiopurines, JAK inhibitors (ruxolitinib, baricitinib, tofacitinib, pacritinib), and RTIs (abacavir, lamivudine, zidovudine) were evaluated using the MTT assay. Results showed that glucocorticoids did not compromise NSC viability. Among thiopurines, thioguanine, but not mercaptopurine, exhibited cytotoxicity in NSCs. All tested JAK inhibitors, except pacritinib, were non-toxic to iPSCs and NSCs. Interestingly, high concentrations of certain JAK inhibitors (ruxolitinib, baricitinib, tofacitinib) led to an unexpected increase in cell viability in AGS patient-derived cells compared to control, suggesting potential alterations in cell proliferation or stress responses. RTIs demonstrated no cytotoxicity, except for zidovudine, which showed selective toxicity in AGS2-derived iPSCs compared to controls. These findings suggest that glucocorticoids, JAK inhibitors (excluding pacritinib), and RTIs are likely safe for NSCs of AGS patients, while caution is warranted with thioguanine and pacritinib. Further studies are needed to explore the mechanisms underlying increased cell viability at high JAK inhibitor concentrations and the selective sensitivity to zidovudine. |
| format | Article |
| id | doaj-art-c82c059c7b4e4e28b6505ad4c548b2ef |
| institution | OA Journals |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-c82c059c7b4e4e28b6505ad4c548b2ef2025-08-20T01:49:32ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-03-011610.3389/fphar.2025.15491831549183Pharmacological evaluation of drug therapies in Aicardi-Goutières syndrome: insights from patient-derived neural stem cellsStefania Braidotti0Rosalba Monica Ferraro1Rosalba Monica Ferraro2Raffaella Franca3Elena Genova4Francesco Giambuzzi5Andrea Mancini6Valentina Marinozzi7Letizia Pugnetti8Giulia Zudeh9Alessandra Tesser10Alberto Tommasini11Alberto Tommasini12Giuliana Decorti13Giuliana Decorti14Silvia Clara Giliani15Silvia Clara Giliani16Gabriele Stocco17Gabriele Stocco18Department of Paediatrics, Institute for Maternal and Child Health (I.R.C.C.S) Burlo Garofolo, Trieste, Italy“Angelo Nocivelli” Institute for Molecular Medicine, ASST Spedali Civili, Brescia, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDepartment of Medical, Surgical and Health Sciences, University of Trieste, Trieste, ItalyDepartment of Paediatrics, Institute for Maternal and Child Health (I.R.C.C.S) Burlo Garofolo, Trieste, ItalyDepartment of Advanced Translational Diagnostics, Institute for Maternal & Child Health (I.R.C.C.S) Burlo Garofolo, Trieste, ItalyDepartment of Medical, Surgical and Health Sciences, University of Trieste, Trieste, ItalyDepartment of Medical, Surgical and Health Sciences, University of Trieste, Trieste, ItalyDepartment of Advanced Translational Diagnostics, Institute for Maternal & Child Health (I.R.C.C.S) Burlo Garofolo, Trieste, ItalyDepartment of Advanced Translational Diagnostics, Institute for Maternal & Child Health (I.R.C.C.S) Burlo Garofolo, Trieste, ItalyDepartment of Paediatrics, Institute for Maternal and Child Health (I.R.C.C.S) Burlo Garofolo, Trieste, ItalyDepartment of Paediatrics, Institute for Maternal and Child Health (I.R.C.C.S) Burlo Garofolo, Trieste, ItalyDepartment of Medical, Surgical and Health Sciences, University of Trieste, Trieste, ItalyDepartment of Medical, Surgical and Health Sciences, University of Trieste, Trieste, ItalyDepartment of Advanced Translational Diagnostics, Institute for Maternal & Child Health (I.R.C.C.S) Burlo Garofolo, Trieste, Italy“Angelo Nocivelli” Institute for Molecular Medicine, ASST Spedali Civili, Brescia, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDepartment of Medical, Surgical and Health Sciences, University of Trieste, Trieste, ItalyDepartment of Advanced Translational Diagnostics, Institute for Maternal & Child Health (I.R.C.C.S) Burlo Garofolo, Trieste, ItalyAicardi-Goutières syndrome (AGS) is a rare genetic disorder classified among type I interferonopathies. Current pharmacological management of AGS is symptomatic and supportive, with recent clinical applications of JAK inhibitors (JAKi) and antiretroviral therapies (RTIs). To investigate the effects of these therapies, patient-specific induced pluripotent stem cells (iPSCs) were generated by reprogramming fibroblasts from three AGS patients with distinct genetic mutations (AGS1, AGS2, AGS7) and differentiated into neural stem cells (NSCs). iPSCs and NSCs derived from commercial BJ fibroblasts of a healthy donor served as control. The cytotoxic effects of glucocorticoids, thiopurines, JAK inhibitors (ruxolitinib, baricitinib, tofacitinib, pacritinib), and RTIs (abacavir, lamivudine, zidovudine) were evaluated using the MTT assay. Results showed that glucocorticoids did not compromise NSC viability. Among thiopurines, thioguanine, but not mercaptopurine, exhibited cytotoxicity in NSCs. All tested JAK inhibitors, except pacritinib, were non-toxic to iPSCs and NSCs. Interestingly, high concentrations of certain JAK inhibitors (ruxolitinib, baricitinib, tofacitinib) led to an unexpected increase in cell viability in AGS patient-derived cells compared to control, suggesting potential alterations in cell proliferation or stress responses. RTIs demonstrated no cytotoxicity, except for zidovudine, which showed selective toxicity in AGS2-derived iPSCs compared to controls. These findings suggest that glucocorticoids, JAK inhibitors (excluding pacritinib), and RTIs are likely safe for NSCs of AGS patients, while caution is warranted with thioguanine and pacritinib. Further studies are needed to explore the mechanisms underlying increased cell viability at high JAK inhibitor concentrations and the selective sensitivity to zidovudine.https://www.frontiersin.org/articles/10.3389/fphar.2025.1549183/fullpatient-derived stem cellAicardi-Goutières syndromedrug sensitivityJAK inhibitorsantiretrovirals |
| spellingShingle | Stefania Braidotti Rosalba Monica Ferraro Rosalba Monica Ferraro Raffaella Franca Elena Genova Francesco Giambuzzi Andrea Mancini Valentina Marinozzi Letizia Pugnetti Giulia Zudeh Alessandra Tesser Alberto Tommasini Alberto Tommasini Giuliana Decorti Giuliana Decorti Silvia Clara Giliani Silvia Clara Giliani Gabriele Stocco Gabriele Stocco Pharmacological evaluation of drug therapies in Aicardi-Goutières syndrome: insights from patient-derived neural stem cells Frontiers in Pharmacology patient-derived stem cell Aicardi-Goutières syndrome drug sensitivity JAK inhibitors antiretrovirals |
| title | Pharmacological evaluation of drug therapies in Aicardi-Goutières syndrome: insights from patient-derived neural stem cells |
| title_full | Pharmacological evaluation of drug therapies in Aicardi-Goutières syndrome: insights from patient-derived neural stem cells |
| title_fullStr | Pharmacological evaluation of drug therapies in Aicardi-Goutières syndrome: insights from patient-derived neural stem cells |
| title_full_unstemmed | Pharmacological evaluation of drug therapies in Aicardi-Goutières syndrome: insights from patient-derived neural stem cells |
| title_short | Pharmacological evaluation of drug therapies in Aicardi-Goutières syndrome: insights from patient-derived neural stem cells |
| title_sort | pharmacological evaluation of drug therapies in aicardi goutieres syndrome insights from patient derived neural stem cells |
| topic | patient-derived stem cell Aicardi-Goutières syndrome drug sensitivity JAK inhibitors antiretrovirals |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1549183/full |
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