Metallothioneins are neuroprotective agents in lysosomal storage disorders

E Cavalca, M Cesani, JC Gifford, M Sena-Esteves, MR Terreni, G Leoncini, M Peviani, A Biffi

Research output: Contribution to journalArticle

Abstract

Objective: Lysosomal storage disorders (LSDs) are a broad class of inherited metabolic diseases caused by the defective activity of lysosomal enzymes. Central nervous system (CNS) manifestations are present in roughly 50% of LSD patients and represent an unmet medical need for them. We explored the therapeutic potential of metallothioneins (MTs), a newly identified family of proteins with reported neuroprotective roles, in the murine models of two LSDs with CNS involvement. Methods: MT-1 overexpressing transgenic mice (MTtg) were crossed with the murine models of Batten and Krabbe diseases. Changes in the survival and manifestations of the disease in the MTtg setting were assessed. In addition, we analyzed the therapeutic effects of MT-1 CNS gene delivery in one of these LSD models. Results: Constitutive expression of MT-1 exerted favorable phenotypic effects in both LSD models. MT-LSD mice showed a 5% to 10% increase in survival and slower disease progression as compared to not-transgenic LSD mice. Rescue of Purkinje cells from degeneration and apoptosis was also observed in the MT-LSD models. This phenotypic amelioration was accompanied by a modulation of the disease-associated activated inflammatory microglia phenotype, and by a reduction of oxidative stress. Importantly, for the clinical translation of our findings, the very same effects were obtained when MTs were delivered to brains by systemic AAV gene transfer. Interpretation: MTs can be considered novel therapeutic agents (and targets) in LSDs and potentiate the effects of approaches aiming at correction of the disease-causing enzyme deficiency in the CNS. Ann Neurol 2018;83:418–432 Ann Neurol 2018;83:418–432. © 2018 American Neurological Association
Original languageEnglish
Pages (from-to)418-432
Number of pages15
JournalAnnals of Neurology
Volume83
Issue number2
DOIs
Publication statusPublished - 2018

Fingerprint

Metallothionein
Neuroprotective Agents
Central Nervous System
Globoid Cell Leukodystrophy
Neuronal Ceroid-Lipofuscinoses
Survival
Purkinje Cells
Central Nervous System Diseases
Metabolic Diseases
Microglia
Therapeutic Uses
Enzymes
Transgenic Mice
Genes
Disease Progression
Oxidative Stress
Apoptosis
Phenotype
Brain
Therapeutics

Cite this

Cavalca, E., Cesani, M., Gifford, JC., Sena-Esteves, M., Terreni, MR., Leoncini, G., ... Biffi, A. (2018). Metallothioneins are neuroprotective agents in lysosomal storage disorders. Annals of Neurology, 83(2), 418-432. https://doi.org/10.1002/ana.25161

Metallothioneins are neuroprotective agents in lysosomal storage disorders. / Cavalca, E; Cesani, M; Gifford, JC; Sena-Esteves, M; Terreni, MR; Leoncini, G; Peviani, M; Biffi, A.

In: Annals of Neurology, Vol. 83, No. 2, 2018, p. 418-432.

Research output: Contribution to journalArticle

Cavalca, E, Cesani, M, Gifford, JC, Sena-Esteves, M, Terreni, MR, Leoncini, G, Peviani, M & Biffi, A 2018, 'Metallothioneins are neuroprotective agents in lysosomal storage disorders', Annals of Neurology, vol. 83, no. 2, pp. 418-432. https://doi.org/10.1002/ana.25161
Cavalca E, Cesani M, Gifford JC, Sena-Esteves M, Terreni MR, Leoncini G et al. Metallothioneins are neuroprotective agents in lysosomal storage disorders. Annals of Neurology. 2018;83(2):418-432. https://doi.org/10.1002/ana.25161
Cavalca, E ; Cesani, M ; Gifford, JC ; Sena-Esteves, M ; Terreni, MR ; Leoncini, G ; Peviani, M ; Biffi, A. / Metallothioneins are neuroprotective agents in lysosomal storage disorders. In: Annals of Neurology. 2018 ; Vol. 83, No. 2. pp. 418-432.
@article{eae1fd70daae44dda55a06c1091fd9f5,
title = "Metallothioneins are neuroprotective agents in lysosomal storage disorders",
abstract = "Objective: Lysosomal storage disorders (LSDs) are a broad class of inherited metabolic diseases caused by the defective activity of lysosomal enzymes. Central nervous system (CNS) manifestations are present in roughly 50{\%} of LSD patients and represent an unmet medical need for them. We explored the therapeutic potential of metallothioneins (MTs), a newly identified family of proteins with reported neuroprotective roles, in the murine models of two LSDs with CNS involvement. Methods: MT-1 overexpressing transgenic mice (MTtg) were crossed with the murine models of Batten and Krabbe diseases. Changes in the survival and manifestations of the disease in the MTtg setting were assessed. In addition, we analyzed the therapeutic effects of MT-1 CNS gene delivery in one of these LSD models. Results: Constitutive expression of MT-1 exerted favorable phenotypic effects in both LSD models. MT-LSD mice showed a 5{\%} to 10{\%} increase in survival and slower disease progression as compared to not-transgenic LSD mice. Rescue of Purkinje cells from degeneration and apoptosis was also observed in the MT-LSD models. This phenotypic amelioration was accompanied by a modulation of the disease-associated activated inflammatory microglia phenotype, and by a reduction of oxidative stress. Importantly, for the clinical translation of our findings, the very same effects were obtained when MTs were delivered to brains by systemic AAV gene transfer. Interpretation: MTs can be considered novel therapeutic agents (and targets) in LSDs and potentiate the effects of approaches aiming at correction of the disease-causing enzyme deficiency in the CNS. Ann Neurol 2018;83:418–432 Ann Neurol 2018;83:418–432. {\circledC} 2018 American Neurological Association",
author = "E Cavalca and M Cesani and JC Gifford and M Sena-Esteves and MR Terreni and G Leoncini and M Peviani and A Biffi",
year = "2018",
doi = "10.1002/ana.25161",
language = "English",
volume = "83",
pages = "418--432",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "2",

}

TY - JOUR

T1 - Metallothioneins are neuroprotective agents in lysosomal storage disorders

AU - Cavalca, E

AU - Cesani, M

AU - Gifford, JC

AU - Sena-Esteves, M

AU - Terreni, MR

AU - Leoncini, G

AU - Peviani, M

AU - Biffi, A

PY - 2018

Y1 - 2018

N2 - Objective: Lysosomal storage disorders (LSDs) are a broad class of inherited metabolic diseases caused by the defective activity of lysosomal enzymes. Central nervous system (CNS) manifestations are present in roughly 50% of LSD patients and represent an unmet medical need for them. We explored the therapeutic potential of metallothioneins (MTs), a newly identified family of proteins with reported neuroprotective roles, in the murine models of two LSDs with CNS involvement. Methods: MT-1 overexpressing transgenic mice (MTtg) were crossed with the murine models of Batten and Krabbe diseases. Changes in the survival and manifestations of the disease in the MTtg setting were assessed. In addition, we analyzed the therapeutic effects of MT-1 CNS gene delivery in one of these LSD models. Results: Constitutive expression of MT-1 exerted favorable phenotypic effects in both LSD models. MT-LSD mice showed a 5% to 10% increase in survival and slower disease progression as compared to not-transgenic LSD mice. Rescue of Purkinje cells from degeneration and apoptosis was also observed in the MT-LSD models. This phenotypic amelioration was accompanied by a modulation of the disease-associated activated inflammatory microglia phenotype, and by a reduction of oxidative stress. Importantly, for the clinical translation of our findings, the very same effects were obtained when MTs were delivered to brains by systemic AAV gene transfer. Interpretation: MTs can be considered novel therapeutic agents (and targets) in LSDs and potentiate the effects of approaches aiming at correction of the disease-causing enzyme deficiency in the CNS. Ann Neurol 2018;83:418–432 Ann Neurol 2018;83:418–432. © 2018 American Neurological Association

AB - Objective: Lysosomal storage disorders (LSDs) are a broad class of inherited metabolic diseases caused by the defective activity of lysosomal enzymes. Central nervous system (CNS) manifestations are present in roughly 50% of LSD patients and represent an unmet medical need for them. We explored the therapeutic potential of metallothioneins (MTs), a newly identified family of proteins with reported neuroprotective roles, in the murine models of two LSDs with CNS involvement. Methods: MT-1 overexpressing transgenic mice (MTtg) were crossed with the murine models of Batten and Krabbe diseases. Changes in the survival and manifestations of the disease in the MTtg setting were assessed. In addition, we analyzed the therapeutic effects of MT-1 CNS gene delivery in one of these LSD models. Results: Constitutive expression of MT-1 exerted favorable phenotypic effects in both LSD models. MT-LSD mice showed a 5% to 10% increase in survival and slower disease progression as compared to not-transgenic LSD mice. Rescue of Purkinje cells from degeneration and apoptosis was also observed in the MT-LSD models. This phenotypic amelioration was accompanied by a modulation of the disease-associated activated inflammatory microglia phenotype, and by a reduction of oxidative stress. Importantly, for the clinical translation of our findings, the very same effects were obtained when MTs were delivered to brains by systemic AAV gene transfer. Interpretation: MTs can be considered novel therapeutic agents (and targets) in LSDs and potentiate the effects of approaches aiming at correction of the disease-causing enzyme deficiency in the CNS. Ann Neurol 2018;83:418–432 Ann Neurol 2018;83:418–432. © 2018 American Neurological Association

U2 - 10.1002/ana.25161

DO - 10.1002/ana.25161

M3 - Article

VL - 83

SP - 418

EP - 432

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 2

ER -