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14 results on '"Barbieri, Miriam"'

2. Therapeutic Efficacy of Mexiletine for Long QT Syndrome Type 2: Evidence From Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes, Transgenic Rabbits, and Patients

Author

Crotti, Lia, Neves, Raquel, Dagradi, Federica, Musu, Giulia, Giannetti, Federica, Bos, J. Martijn, Barbieri, Miriam, Cerea, Paolo, Giovenzana, Fulvio L.F., Torchio, Margherita, Mura, Manuela, Gnecchi, Massimiliano, Conte, Giulio, Auricchio, Angelo, Sala, Luca, Odening, Katja E., Ackerman, Michael J., and Schwartz, Peter J.

Published
2024
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3. KCNQ1 suppression-replacement gene therapy in transgenic rabbits with type 1 long QT syndrome.

Author

Bains, Sahej, Giammarino, Lucilla, Nimani, Saranda, Alerni, Nicolo, Tester, David J, Kim, C S John, Christoforou, Nicolas, Louradour, Julien, Horváth, András, Beslac, Olgica, Barbieri, Miriam, Matas, Lluis, Hof, Thomas S, Lopez, Ruben, Perez-Feliz, Stefanie, Parodi, Chiara, Casalta, Luisana G Garcia, Jurgensen, Jacqulyn, Barry, Michael A, and Bego, Mariana

Subjects
LONG QT syndrome, ACTION potentials, GENE therapy, POTASSIUM channels, INTRAVENOUS therapy
Abstract

Background and Aims Type 1 long QT syndrome (LQT1) is caused by pathogenic variants in the KCNQ1- encoded Kv7.1 potassium channels, which pathologically prolong ventricular action potential duration (APD). Herein, the pathologic phenotype in transgenic LQT1 rabbits is rescued using a novel KCNQ1 suppression-replacement (SupRep) gene therapy. Methods KCNQ1 -SupRep gene therapy was developed by combining into a single construct a KCNQ1 shRNA (suppression) and an shRNA-immune KCNQ1 cDNA (replacement), packaged into adeno-associated virus serotype 9, and delivered in vivo via an intra-aortic root injection (1E10 vg/kg). To ascertain the efficacy of SupRep, 12-lead electrocardiograms were assessed in adult LQT1 and wild-type (WT) rabbits and patch-clamp experiments were performed on isolated ventricular cardiomyocytes. Results KCNQ1 -SupRep treatment of LQT1 rabbits resulted in significant shortening of the pathologically prolonged QT index (QTi) towards WT levels. Ventricular cardiomyocytes isolated from treated LQT1 rabbits demonstrated pronounced shortening of APD compared to LQT1 controls, leading to levels similar to WT (LQT1-UT vs. LQT1-SupRep, P <.0001, LQT1-SupRep vs. WT, P = ns). Under β-adrenergic stimulation with isoproterenol, SupRep-treated rabbits demonstrated a WT-like physiological QTi and APD90 behaviour. Conclusions This study provides the first animal-model, proof-of-concept gene therapy for correction of LQT1. In LQT1 rabbits, treatment with KCNQ1 -SupRep gene therapy normalized the clinical QTi and cellular APD90 to near WT levels both at baseline and after isoproterenol. If similar QT/APD correction can be achieved with intravenous administration of KCNQ1- SupRep gene therapy in LQT1 rabbits, these encouraging data should compel continued development of this gene therapy for patients with LQT1. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Simultaneous assessment of mechanical and electrical function in Langendorff-perfused ex-vivo mouse hearts

Author

Louradour, Julien, primary, Ottersberg, Rahel, additional, Segiser, Adrian, additional, Olejnik, Agnieszka, additional, Martínez-Salazar, Berenice, additional, Siegrist, Mark, additional, Egle, Manuel, additional, Barbieri, Miriam, additional, Nimani, Saranda, additional, Alerni, Nicolò, additional, Döring, Yvonne, additional, Odening, Katja E., additional, and Longnus, Sarah, additional

Published
2023
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5. PO-02-210 AAV9-MEDIATED -SUPPRESSION-REPLACEMENT GENE THERAPY IN TRANSGENIC RABBITS WITH TYPE 1 LONG QT SYNDROME

Author

Bains, Sahej, primary, Giammarino, Lucilla, additional, Nimani, Saranda, additional, Alerni, Nicolo, additional, Tester, David, additional, Christoforou, Nicolas, additional, Louradour, Julien, additional, Hof, Thomas S., additional, Beslac, Olgica, additional, Barbieri, Miriam, additional, Matas, Lluis, additional, Horvath, Andras, additional, Lopez, Ruben, additional, Perez-Feliz, Stefanie, additional, Kim, Changsung J., additional, Zhou, Wei, additional, Ye, Dan, additional, Jurgensen, Jacqulyn, additional, Barry, Michael A., additional, Bego, Mariana, additional, Keyes, Lisa, additional, Owens, Jane, additional, Pinkstaff, Jason, additional, Koren, Gideon, additional, Zehender, Manfred, additional, Brunner, Michael, additional, Casoni, Daniela, additional, Praz, Fabien, additional, Haeberlin, Andreas, additional, Brooks, Gabriel, additional, Odening, Katja E., additional, and Ackerman, Michael J., additional

Published
2023
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6. Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2

Author

Giannetti, Federica, primary, Barbieri, Miriam, additional, Shiti, Assad, additional, Casini, Simona, additional, Sager, Philip T, additional, Das, Saumya, additional, Pradhananga, Sabindra, additional, Srinivasan, Dinesh, additional, Nimani, Saranda, additional, Alerni, Nicolò, additional, Louradour, Julien, additional, Mura, Manuela, additional, Gnecchi, Massimiliano, additional, Brink, Paul, additional, Zehender, Manfred, additional, Koren, Gideon, additional, Zaza, Antonio, additional, Crotti, Lia, additional, Wilde, Arthur A M, additional, Schwartz, Peter J, additional, Remme, Carol Ann, additional, Gepstein, Lior, additional, Sala, Luca, additional, and Odening, Katja E, additional

Published
2023
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7. Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2

Author

Giannetti, F, Barbieri, M, Shiti, A, Casini, S, Sager, P, Das, S, Pradhananga, S, Srinivasan, D, Nimani, S, Alerni, N, Louradour, J, Mura, M, Gnecchi, M, Brink, P, Zehender, M, Koren, G, Zaza, A, Crotti, L, Wilde, A, Schwartz, P, Remme, C, Gepstein, L, Sala, L, Odening, K, Giannetti, Federica, Barbieri, Miriam, Shiti, Assad, Casini, Simona, Sager, Philip T, Das, Saumya, Pradhananga, Sabindra, Srinivasan, Dinesh, Nimani, Saranda, Alerni, Nicolò, Louradour, Julien, Mura, Manuela, Gnecchi, Massimiliano, Brink, Paul, Zehender, Manfred, Koren, Gideon, Zaza, Antonio, Crotti, Lia, Wilde, Arthur A M, Schwartz, Peter J, Remme, Carol Ann, Gepstein, Lior, Sala, Luca, Odening, Katja E, Giannetti, F, Barbieri, M, Shiti, A, Casini, S, Sager, P, Das, S, Pradhananga, S, Srinivasan, D, Nimani, S, Alerni, N, Louradour, J, Mura, M, Gnecchi, M, Brink, P, Zehender, M, Koren, G, Zaza, A, Crotti, L, Wilde, A, Schwartz, P, Remme, C, Gepstein, L, Sala, L, Odening, K, Giannetti, Federica, Barbieri, Miriam, Shiti, Assad, Casini, Simona, Sager, Philip T, Das, Saumya, Pradhananga, Sabindra, Srinivasan, Dinesh, Nimani, Saranda, Alerni, Nicolò, Louradour, Julien, Mura, Manuela, Gnecchi, Massimiliano, Brink, Paul, Zehender, Manfred, Koren, Gideon, Zaza, Antonio, Crotti, Lia, Wilde, Arthur A M, Schwartz, Peter J, Remme, Carol Ann, Gepstein, Lior, Sala, Luca, and Odening, Katja E

Abstract

AIMS: Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2. METHODS AND RESULTS: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM-10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3-10 µM (by 20-32%/25-30%/44-45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3-3 µM. CONCLUSION: A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS.

Published
2023

8. Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2

Author

Giannetti, Federica, Barbieri, Miriam, Shiti, Assad, Casini, Simona, Sager, Philip T, Das, Saumya, Pradhananga, Sabindra, Srinivasan, Dinesh, Nimani, Saranda, Alerni, Nicolò, Louradour, Julien, Mura, Manuela, Gnecchi, Massimiliano, Brink, Paul, Zehender, Manfred, Koren, Gideon, Zaza, Antonio, Crotti, Lia, Wilde, Arthur A M, Schwartz, Peter J, Remme, Carol Ann, Gepstein, Lior, Sala, Luca, Odening, Katja E, Giannetti, F, Barbieri, M, Shiti, A, Casini, S, Sager, P, Das, S, Pradhananga, S, Srinivasan, D, Nimani, S, Alerni, N, Louradour, J, Mura, M, Gnecchi, M, Brink, P, Zehender, M, Koren, G, Zaza, A, Crotti, L, Wilde, A, Schwartz, P, Remme, C, Gepstein, L, Sala, L, and Odening, K

Subjects
Cellular electrophysiology, Physiology (medical), LQTS, Animal model, 610 Medicine & health, 610 Medizin und Gesundheit, Cardiology and Cardiovascular Medicine, Genotype-specific therapy, hiPSC, Mechanism-based therapy
Abstract

Aims Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2. Methods and results Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM–10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3–10 µM (by 20–32%/25–30%/44–45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3–3 µM. Conclusion A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS.

Published
2023
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10. EN-482891-004 AAV9-MEDIATED KCNH2-SUPPRESSION-REPLACEMENT GENE THERAPY PROLONGS THE PATHOLOGICALLY SHORTENED QT/APD IN SHORT QT SYNDROME TYPE 1 RABBIT MODELS

Author

Nimani, Saranda, Bains, Sahej, Alerni, Nicolo, Giammarino, Lucilla, Horváth, András, Louradour, Julien, Barbieri, Miriam, Beslac, Olgica, Egle, Manuel, Tester, David, Christoforou, Nicolas, Matas, Lluis, Lopez, Ruben, Perez-Feliz, Stefanie, Kim, Changsung J., Zhou, Wei, Ye, Dan, Jurgensen, Jacqulyn, Barry, Michael, Bego, Mariana, Keyes, Lisa, Owens, Jane, Pinkstaff, Jason, Zehender, Manfred, Brunner, Michael, Casoni, Daniela, Praz, Fabien, Haeberlin, Andreas, Brooks, Gabriel, Ackerman, Michael J., and Odening, Katja E.

Published
2024
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11. PO-02-210 AAV9-MEDIATED KCNQ1-SUPPRESSION-REPLACEMENT GENE THERAPY IN TRANSGENIC RABBITS WITH TYPE 1 LONG QT SYNDROME

Author

Bains, Sahej, Giammarino, Lucilla, Nimani, Saranda, Alerni, Nicolo, Tester, David, Christoforou, Nicolas, Louradour, Julien, Hof, Thomas S., Beslac, Olgica, Barbieri, Miriam, Matas, Lluis, Horvath, Andras, Lopez, Ruben, Perez-Feliz, Stefanie, Kim, Changsung J., Zhou, Wei, Ye, Dan, Jurgensen, Jacqulyn, Barry, Michael A., Bego, Mariana, Keyes, Lisa, Owens, Jane, Pinkstaff, Jason, Koren, Gideon, Zehender, Manfred, Brunner, Michael, Casoni, Daniela, Praz, Fabien, Haeberlin, Andreas, Brooks, Gabriel, Odening, Katja E., and Ackerman, Michael J.

Published
2023
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