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April 09, 2019; 92 (15 Supplement) May 9, 2019

mTORc1 but not JNK Inhibition Augments Glucocorticosteroid Efficacy in Multiple Sclerosis (S55.004)

Robert Hoepner, Maud Bagnoud, Maximilian Pistor, Anke Salmen, Myriam Briner, Lisa Schrewe, Kirsten Guse, Farhad Ahmadi, Seray Demir, Louise Laverick, Melissa Gresle, Paul Worley, Holger Reichardt, Helmut Butzkueven, Ralf Gold, Fred Lühder, Andrew Chan
First published April 16, 2019,
Robert Hoepner
1Inselspital Bern Switzerland
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Maud Bagnoud
1Inselspital Bern Switzerland
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Maximilian Pistor
1Inselspital Bern Switzerland
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Anke Salmen
1Inselspital Bern Switzerland
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Myriam Briner
1Inselspital Bern Switzerland
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Lisa Schrewe
1Inselspital Bern Switzerland
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Kirsten Guse
1Inselspital Bern Switzerland
2Ruhr University Bern Switzerland
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Farhad Ahmadi
1Inselspital Bern Switzerland
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Seray Demir
2Ruhr University Bern Switzerland
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Louise Laverick
3Royal Melbourne Hospital Melbourne Bahrain
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Melissa Gresle
3Royal Melbourne Hospital Melbourne Bahrain
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Paul Worley
4John Hopkins University Baltimore MD United States
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Holger Reichardt
5University Medical Center Goettingen Goettingen Germany
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Helmut Butzkueven
6Monash University Parkville Australia
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Ralf Gold
7Neurologische Universitaetsklinik Bochum Germany
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Fred Lühder
5University Medical Center Goettingen Goettingen Germany
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Andrew Chan
1Inselspital Bern Switzerland
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Citation
mTORc1 but not JNK Inhibition Augments Glucocorticosteroid Efficacy in Multiple Sclerosis (S55.004)
Robert Hoepner, Maud Bagnoud, Maximilian Pistor, Anke Salmen, Myriam Briner, Lisa Schrewe, Kirsten Guse, Farhad Ahmadi, Seray Demir, Louise Laverick, Melissa Gresle, Paul Worley, Holger Reichardt, Helmut Butzkueven, Ralf Gold, Fred Lühder, Andrew Chan
Neurology Apr 2019, 92 (15 Supplement) S55.004;

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Abstract

Objective: We investigated potential strategies to enhance steroid efficacy in multiple sclerosis relpases.

Background: Glucocorticoids are mainly used for treatment of multiple sclerosis relapses. However, increase of disability following acute disease phases is commonly observed.

Design/Methods: In vitro human and murine T cell apoptosis and in vivo MOG35–55 Experimental Autoimmune Encephalomyelitis (EAE) were used to investigate if mTORc1 or JNK inhibition increases glucocorticoid efficacy. Positive results of the screening experiments were then in vitro and in vivo confirmed taking advantage of conditional knockout mice with T-cell specific deficiency for mTORc1 or the glucocorticoid receptor. Glucocorticoid receptor concentration was measured using an ELISA. The potential to inhibit mTORc1 was checked by analysing phosphorylation of a downstream target of the mTORc1 pathway.

Results: mTORc1 inhibition using different drugs (everolimus, rapamycin, voxtalisib, XL388, vitamin D) but not JNK inhibition by SP600125 (SP) lead to an increase of human T cell apoptosis in vitro. In contrast to SP/glucocorticoids dual treatment, combination therapy of everolimus and methylprednisolone ameliorates EAE disease course compared to respective monotherapies. Mechanistically, the increased effects of glucocorticoids were caused by an upregulation of the glucocorticoid receptor protein via mTORc1. Relevance of the glucocorticoid receptor was validated in mice with T-cell specific glucocorticoid receptor deficiency. Here methylprednisolone treatment had no therapeutic effect on EAE disease course. Finally, in addition to pharmacological inhibition the relevance of the mTORc1 pathway was also investigated using mice with T-cell specific deficiency of mTORc1 activity. In these mice, the pharmacological inhibition of mTORc1 did not lead to an upregulation of the glucocorticoid receptor and combination therapy with methylprednisolone did not ameliorate clinical course of EAE disease.

Conclusions: mTORc1 inhibition seems to increase therapeutic efficacy of glucocorticoids via an upregulation of the glucocorticoid receptor. Our data suggest that transient mTORc1 inhibition might be used to overcome glucocorticoid resistance in patients with multiple sclerosis.

Disclosure: Dr. Hoepner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis and Biogen Idec. He also received speaker’s honoraria from Biogen, Novartis, Merk and Almirall. Dr. Hoepner has received research support from Novartis and Biogen Idec. Dr. Bagnoud has nothing to disclose. Dr. Pistor has nothing to disclose. Dr. Salmen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Almirall Hermal GmbH, Biogen, Merck, Novartis, Roche and Sanofi Genzyme. Dr. Briner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck and Biogen. Dr. Schrewe has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sanofi Genzyme. Dr. Guse has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Ahmadi has nothing to disclose. Dr. Demir has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sanofi Genzyme. Dr. Laverick has nothing to disclose. Dr. Gresle has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen Idec, Novartis, and Sanofi-Aventis Pharmaceuticals, Inc. Dr. Worley has nothing to disclose. Dr. Reichardt has nothing to disclose. Dr. Butzkueven has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Merck, Roche, Novartis, Teva, Oxford Pharamgenesis. Dr. Butzkueven has received research support from Novartis, Biogen, Merck, NHMRC Australia, MS Research Australia, UK MS Trust. Dr. Gold has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Baxter, Bayer Schering, Biogen, CLB Behring, Celgene, Genzyme, Merck Serono, Novartis, Roche, Stendhal, Talecris, and Teva Pharmaceuticals. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Diseases, Experimental Neurology and the Journal of Neuroimmunology. Dr. Gold has received research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer, Schering Pharma, Genzyme, Merck Serono, and Novartis. Dr. Luhder has nothing to disclose. Dr. Chan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Bayer, Biogen, Genzyme, Merck, Novartis, Roche, Teva, Swiss National Fonds, Genzyme and UCB, Clinical and translational neuroscience and the Journal of International medical research. Dr. Chan has received research support from Bayer, Biogen, Genzyme, Merck, Novartis, Roche, Teva, Swiss National Fonds, Genzyme and UCB, Clinical and translational neuroscience and the Journal of International medical research.

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