Repurposing the cardiac glycoside digoxin to stimulate myelin regeneration in chemically-induced and immune-mediated mouse models of multiple sclerosis

Haley E. Titus; Huan Xu; Andrew Patrick Robinson; Priyam A. Patel; Yanan Chen; Damiano Fantini; Valerie Eaton; Molly Karl; Eric D. Garrison; Indigo V.L. Rose; Ming Yi Chiang; Joseph R. Podojil; Roumen Balabanov; Shane A. Liddelow; Robert H. Miller; Brian Popko; Stephen D Miller

doi:10.1002/glia.24231

Repurposing the cardiac glycoside digoxin to stimulate myelin regeneration in chemically-induced and immune-mediated mouse models of multiple sclerosis

Haley E. Titus, Huan Xu, Andrew Patrick Robinson, Priyam A. Patel, Yanan Chen, Damiano Fantini, Valerie Eaton, Molly Karl, Eric D. Garrison, Indigo V.L. Rose, Ming Yi Chiang, Joseph R. Podojil, Roumen Balabanov, Shane A. Liddelow, Robert H. Miller, Brian Popko, Stephen D Miller^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by inflammation, demyelination, and neurodegeneration. The ideal MS therapy would both specifically inhibit the underlying autoimmune response and promote repair/regeneration of myelin as well as maintenance of axonal integrity. Currently approved MS therapies consist of non-specific immunosuppressive molecules/antibodies which block activation or CNS homing of autoreactive T cells, but there are no approved therapies for stimulation of remyelination nor maintenance of axonal integrity. In an effort to repurpose an FDA-approved medication for myelin repair, we chose to examine the effectiveness of digoxin, a cardiac glycoside (Na⁺/K⁺ ATPase inhibitor), originally identified as pro-myelinating in an in vitro screen. We found that digoxin regulated multiple genes in oligodendrocyte progenitor cells (OPCs) essential for oligodendrocyte (OL) differentiation in vitro, promoted OL differentiation both in vitro and in vivo in female naïve C57BL/6J (B6) mice, and stimulated recovery of myelinated axons in B6 mice following demyelination in the corpus callosum induced by cuprizone and spinal cord demyelination induced by lysophosphatidylcholine (LPC), respectively. More relevant to treatment of MS, we show that digoxin treatment of mice with established MOG_35-55-induced Th1/Th17-mediated chronic EAE combined with tolerance induced by the i.v. infusion of biodegradable poly(lactide-co-glycolide) nanoparticles coupled with MOG_35-55 (PLG-MOG_35-55) completely ameliorated clinical disease symptoms and stimulated recovery of OL lineage cell numbers. These findings provide critical pre-clinical evidence supporting future clinical trials of myelin-specific tolerance with myelin repair/regeneration drugs, such as digoxin, in MS patients.

Original language	English (US)
Pages (from-to)	1950-1970
Number of pages	21
Journal	Glia
Volume	70
Issue number	10
DOIs	https://doi.org/10.1002/glia.24231
State	Published - Oct 2022

Funding

We acknowledge the Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Core Facility for the assistance of data acquisition, the Northwestern University Center for Advanced Microscopy for the assistance of data acquisition, the Northwestern University NUSeq Core Facility for the assistance of data acquisition, the Northwestern University Quantitative Data Science Core for the assistance of data acquisition and analysis, and the George Washington University Nanofabrication and Imaging Center for the assistance of data acquisition. We thank Miller laboratory members for all of their support and insight. This work was supported by NIH Grants R01 NS099334 and R21 AI142059 (Miller, S.D., PI), National Multiple Sclerosis Society (NMSS) Post-Doctoral Fellowship FG 20125-A-1 (Titus, H.E., PI), R01 NS109372 (BP), NMSS RG-1807-32005 (BP). We also acknowledge the Johnnie Walker's MS Foundation (SDM), the David & Amy Fulton Foundation (SDM), and the Crammer Family Foundation (SDM), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (BP), the Rampy MS Research Foundation (BP), the NYU School of Medicine (SAL), The Blas Frangione Foundation (SAL), the Cure Alzheimer's Fund (SAL), anonymous donors (SAL), and the Novartis Institute for Biomedical Research (SAL). We acknowledge the Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Core Facility for the assistance of data acquisition, the Northwestern University Center for Advanced Microscopy for the assistance of data acquisition, the Northwestern University NUSeq Core Facility for the assistance of data acquisition, the Northwestern University Quantitative Data Science Core for the assistance of data acquisition and analysis, and the George Washington University Nanofabrication and Imaging Center for the assistance of data acquisition. We thank Miller laboratory members for all of their support and insight. This work was supported by NIH Grants R01 NS099334 and R21 AI142059 (Miller, S.D., PI), National Multiple Sclerosis Society (NMSS) Post‐Doctoral Fellowship FG 20125‐A‐1 (Titus, H.E., PI), R01 NS109372 (BP), NMSS RG‐1807‐32005 (BP). We also acknowledge the Johnnie Walker's MS Foundation (SDM), the David & Amy Fulton Foundation (SDM), and the Crammer Family Foundation (SDM), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (BP), the Rampy MS Research Foundation (BP), the NYU School of Medicine (SAL), The Blas Frangione Foundation (SAL), the Cure Alzheimer's Fund (SAL), anonymous donors (SAL), and the Novartis Institute for Biomedical Research (SAL).

Keywords

digoxin
immune tolerance
multiple sclerosis
myelin regeneration
oligodendrocyte

ASJC Scopus subject areas

Neurology
Cellular and Molecular Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/glia.24231

Cite this

Titus, H. E., Xu, H., Robinson, A. P., Patel, P. A., Chen, Y., Fantini, D., Eaton, V., Karl, M., Garrison, E. D., Rose, I. V. L., Chiang, M. Y., Podojil, J. R., Balabanov, R., Liddelow, S. A., Miller, R. H., Popko, B., & Miller, S. D. (2022). Repurposing the cardiac glycoside digoxin to stimulate myelin regeneration in chemically-induced and immune-mediated mouse models of multiple sclerosis. Glia, 70(10), 1950-1970. https://doi.org/10.1002/glia.24231

@article{b5b8dc6a665e4289bfea656424924c18,

title = "Repurposing the cardiac glycoside digoxin to stimulate myelin regeneration in chemically-induced and immune-mediated mouse models of multiple sclerosis",

abstract = "Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by inflammation, demyelination, and neurodegeneration. The ideal MS therapy would both specifically inhibit the underlying autoimmune response and promote repair/regeneration of myelin as well as maintenance of axonal integrity. Currently approved MS therapies consist of non-specific immunosuppressive molecules/antibodies which block activation or CNS homing of autoreactive T cells, but there are no approved therapies for stimulation of remyelination nor maintenance of axonal integrity. In an effort to repurpose an FDA-approved medication for myelin repair, we chose to examine the effectiveness of digoxin, a cardiac glycoside (Na+/K+ ATPase inhibitor), originally identified as pro-myelinating in an in vitro screen. We found that digoxin regulated multiple genes in oligodendrocyte progenitor cells (OPCs) essential for oligodendrocyte (OL) differentiation in vitro, promoted OL differentiation both in vitro and in vivo in female na{\"i}ve C57BL/6J (B6) mice, and stimulated recovery of myelinated axons in B6 mice following demyelination in the corpus callosum induced by cuprizone and spinal cord demyelination induced by lysophosphatidylcholine (LPC), respectively. More relevant to treatment of MS, we show that digoxin treatment of mice with established MOG35-55-induced Th1/Th17-mediated chronic EAE combined with tolerance induced by the i.v. infusion of biodegradable poly(lactide-co-glycolide) nanoparticles coupled with MOG35-55 (PLG-MOG35-55) completely ameliorated clinical disease symptoms and stimulated recovery of OL lineage cell numbers. These findings provide critical pre-clinical evidence supporting future clinical trials of myelin-specific tolerance with myelin repair/regeneration drugs, such as digoxin, in MS patients.",

keywords = "digoxin, immune tolerance, multiple sclerosis, myelin regeneration, oligodendrocyte",

author = "Titus, {Haley E.} and Huan Xu and Robinson, {Andrew Patrick} and Patel, {Priyam A.} and Yanan Chen and Damiano Fantini and Valerie Eaton and Molly Karl and Garrison, {Eric D.} and Rose, {Indigo V.L.} and Chiang, {Ming Yi} and Podojil, {Joseph R.} and Roumen Balabanov and Liddelow, {Shane A.} and Miller, {Robert H.} and Brian Popko and Miller, {Stephen D}",

note = "Funding Information: We acknowledge the Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Core Facility for the assistance of data acquisition, the Northwestern University Center for Advanced Microscopy for the assistance of data acquisition, the Northwestern University NUSeq Core Facility for the assistance of data acquisition, the Northwestern University Quantitative Data Science Core for the assistance of data acquisition and analysis, and the George Washington University Nanofabrication and Imaging Center for the assistance of data acquisition. We thank Miller laboratory members for all of their support and insight. This work was supported by NIH Grants R01 NS099334 and R21 AI142059 (Miller, S.D., PI), National Multiple Sclerosis Society (NMSS) Post‐Doctoral Fellowship FG 20125‐A‐1 (Titus, H.E., PI), R01 NS109372 (BP), NMSS RG‐1807‐32005 (BP). We also acknowledge the Johnnie Walker's MS Foundation (SDM), the David & Amy Fulton Foundation (SDM), and the Crammer Family Foundation (SDM), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (BP), the Rampy MS Research Foundation (BP), the NYU School of Medicine (SAL), The Blas Frangione Foundation (SAL), the Cure Alzheimer's Fund (SAL), anonymous donors (SAL), and the Novartis Institute for Biomedical Research (SAL). Publisher Copyright: {\textcopyright} 2022 The Authors. GLIA published by Wiley Periodicals LLC.",

year = "2022",

month = oct,

doi = "10.1002/glia.24231",

language = "English (US)",

volume = "70",

pages = "1950--1970",

journal = "Glia",

issn = "0894-1491",

publisher = "John Wiley & Sons Inc.",

number = "10",

}

Titus, HE, Xu, H, Robinson, AP, Patel, PA, Chen, Y, Fantini, D, Eaton, V, Karl, M, Garrison, ED, Rose, IVL, Chiang, MY, Podojil, JR , Balabanov, R, Liddelow, SA, Miller, RH, Popko, B & Miller, SD 2022, 'Repurposing the cardiac glycoside digoxin to stimulate myelin regeneration in chemically-induced and immune-mediated mouse models of multiple sclerosis', Glia, vol. 70, no. 10, pp. 1950-1970. https://doi.org/10.1002/glia.24231

TY - JOUR

T1 - Repurposing the cardiac glycoside digoxin to stimulate myelin regeneration in chemically-induced and immune-mediated mouse models of multiple sclerosis

AU - Titus, Haley E.

AU - Xu, Huan

AU - Robinson, Andrew Patrick

AU - Patel, Priyam A.

AU - Chen, Yanan

AU - Fantini, Damiano

AU - Eaton, Valerie

AU - Karl, Molly

AU - Garrison, Eric D.

AU - Rose, Indigo V.L.

AU - Chiang, Ming Yi

AU - Podojil, Joseph R.

AU - Balabanov, Roumen

AU - Liddelow, Shane A.

AU - Miller, Robert H.

AU - Popko, Brian

AU - Miller, Stephen D

N1 - Funding Information: We acknowledge the Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Core Facility for the assistance of data acquisition, the Northwestern University Center for Advanced Microscopy for the assistance of data acquisition, the Northwestern University NUSeq Core Facility for the assistance of data acquisition, the Northwestern University Quantitative Data Science Core for the assistance of data acquisition and analysis, and the George Washington University Nanofabrication and Imaging Center for the assistance of data acquisition. We thank Miller laboratory members for all of their support and insight. This work was supported by NIH Grants R01 NS099334 and R21 AI142059 (Miller, S.D., PI), National Multiple Sclerosis Society (NMSS) Post‐Doctoral Fellowship FG 20125‐A‐1 (Titus, H.E., PI), R01 NS109372 (BP), NMSS RG‐1807‐32005 (BP). We also acknowledge the Johnnie Walker's MS Foundation (SDM), the David & Amy Fulton Foundation (SDM), and the Crammer Family Foundation (SDM), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (BP), the Rampy MS Research Foundation (BP), the NYU School of Medicine (SAL), The Blas Frangione Foundation (SAL), the Cure Alzheimer's Fund (SAL), anonymous donors (SAL), and the Novartis Institute for Biomedical Research (SAL). Publisher Copyright: © 2022 The Authors. GLIA published by Wiley Periodicals LLC.

PY - 2022/10

Y1 - 2022/10

N2 - Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by inflammation, demyelination, and neurodegeneration. The ideal MS therapy would both specifically inhibit the underlying autoimmune response and promote repair/regeneration of myelin as well as maintenance of axonal integrity. Currently approved MS therapies consist of non-specific immunosuppressive molecules/antibodies which block activation or CNS homing of autoreactive T cells, but there are no approved therapies for stimulation of remyelination nor maintenance of axonal integrity. In an effort to repurpose an FDA-approved medication for myelin repair, we chose to examine the effectiveness of digoxin, a cardiac glycoside (Na+/K+ ATPase inhibitor), originally identified as pro-myelinating in an in vitro screen. We found that digoxin regulated multiple genes in oligodendrocyte progenitor cells (OPCs) essential for oligodendrocyte (OL) differentiation in vitro, promoted OL differentiation both in vitro and in vivo in female naïve C57BL/6J (B6) mice, and stimulated recovery of myelinated axons in B6 mice following demyelination in the corpus callosum induced by cuprizone and spinal cord demyelination induced by lysophosphatidylcholine (LPC), respectively. More relevant to treatment of MS, we show that digoxin treatment of mice with established MOG35-55-induced Th1/Th17-mediated chronic EAE combined with tolerance induced by the i.v. infusion of biodegradable poly(lactide-co-glycolide) nanoparticles coupled with MOG35-55 (PLG-MOG35-55) completely ameliorated clinical disease symptoms and stimulated recovery of OL lineage cell numbers. These findings provide critical pre-clinical evidence supporting future clinical trials of myelin-specific tolerance with myelin repair/regeneration drugs, such as digoxin, in MS patients.

AB - Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by inflammation, demyelination, and neurodegeneration. The ideal MS therapy would both specifically inhibit the underlying autoimmune response and promote repair/regeneration of myelin as well as maintenance of axonal integrity. Currently approved MS therapies consist of non-specific immunosuppressive molecules/antibodies which block activation or CNS homing of autoreactive T cells, but there are no approved therapies for stimulation of remyelination nor maintenance of axonal integrity. In an effort to repurpose an FDA-approved medication for myelin repair, we chose to examine the effectiveness of digoxin, a cardiac glycoside (Na+/K+ ATPase inhibitor), originally identified as pro-myelinating in an in vitro screen. We found that digoxin regulated multiple genes in oligodendrocyte progenitor cells (OPCs) essential for oligodendrocyte (OL) differentiation in vitro, promoted OL differentiation both in vitro and in vivo in female naïve C57BL/6J (B6) mice, and stimulated recovery of myelinated axons in B6 mice following demyelination in the corpus callosum induced by cuprizone and spinal cord demyelination induced by lysophosphatidylcholine (LPC), respectively. More relevant to treatment of MS, we show that digoxin treatment of mice with established MOG35-55-induced Th1/Th17-mediated chronic EAE combined with tolerance induced by the i.v. infusion of biodegradable poly(lactide-co-glycolide) nanoparticles coupled with MOG35-55 (PLG-MOG35-55) completely ameliorated clinical disease symptoms and stimulated recovery of OL lineage cell numbers. These findings provide critical pre-clinical evidence supporting future clinical trials of myelin-specific tolerance with myelin repair/regeneration drugs, such as digoxin, in MS patients.

KW - digoxin

KW - immune tolerance

KW - multiple sclerosis

KW - myelin regeneration

KW - oligodendrocyte

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VL - 70

SP - 1950

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ER -

Repurposing the cardiac glycoside digoxin to stimulate myelin regeneration in chemically-induced and immune-mediated mouse models of multiple sclerosis

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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