Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses

Thomas Kirkegaard; James Gray; David A. Priestman; Kerri Lee Wallom; Jennifer Atkins; Ole Dines Olsen; Alexander Klein; Svetlana Drndarski; Nikolaj H T Petersen; Linda Ingemann; David A. Smith; Lauren Morris; Claus Bornæs; Signe Humle Jørgensen; Ian Williams; Anders Hinsby; Christoph Arenz; David Begley; Marja Jäättelä; Frances M. Platt

doi:10.1126/scitranslmed.aad9823

Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses

Thomas Kirkegaard^*, James Gray, David A. Priestman, Kerri Lee Wallom, Jennifer Atkins, Ole Dines Olsen, Alexander Klein, Svetlana Drndarski, Nikolaj H T Petersen, Linda Ingemann, David A. Smith, Lauren Morris, Claus Bornæs, Signe Humle Jørgensen, Ian Williams, Anders Hinsby, Christoph Arenz, David Begley, Marja Jäättelä, Frances M. Platt

^*Corresponding author for this work

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

122 Citations (Scopus)

Abstract

Lysosomal storage diseases (LSDs) often manifest with severe systemic and central nervous system (CNS) symptoms. The existing treatment options are limited and have no or only modest efficacy against neurological manifestations of disease. We demonstrate that recombinant human heat shock protein 70 (HSP70) improves the binding of several sphingolipid-degrading enzymes to their essential cofactor bis(monoacyl)glycerophosphate in vitro. HSP70 treatment reversed lysosomal pathology in primary fibroblasts from 14 patients with eight different LSDs. HSP70 penetrated effectively into murine tissues including the CNS and inhibited glycosphingolipid accumulation in murine models of Fabry disease (Gla^-/-), Sandhoff disease (Hexb^-/-), and Niemann-Pick disease type C (Npc1^-/-) and attenuated a wide spectrum of disease-associated neurological symptoms in Hexb^-/- and Npc1^-/- mice. Oral administration of arimoclomol, a small-molecule coinducer of HSPs that is currently in clinical trials for Niemann-Pick disease type C (NPC), recapitulated the effects of recombinant human HSP70, suggesting that heat shock protein-based therapies merit clinical evaluation for treating LSDs.

Original language	English
Article number	355ra118
Journal	Science Translational Medicine
Volume	8
Issue number	355
DOIs	https://doi.org/10.1126/scitranslmed.aad9823
Publication status	Published - 7 Sept 2016

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Kirkegaard, T., Gray, J., Priestman, D. A., Wallom, K. L., Atkins, J., Olsen, O. D., Klein, A., Drndarski, S., Petersen, N. H. T., Ingemann, L., Smith, D. A., Morris, L., Bornæs, C., Jørgensen, S. H., Williams, I., Hinsby, A., Arenz, C., Begley, D., Jäättelä, M., & Platt, F. M. (2016). Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses. Science Translational Medicine, 8(355), Article 355ra118. https://doi.org/10.1126/scitranslmed.aad9823

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abstract = "Lysosomal storage diseases (LSDs) often manifest with severe systemic and central nervous system (CNS) symptoms. The existing treatment options are limited and have no or only modest efficacy against neurological manifestations of disease. We demonstrate that recombinant human heat shock protein 70 (HSP70) improves the binding of several sphingolipid-degrading enzymes to their essential cofactor bis(monoacyl)glycerophosphate in vitro. HSP70 treatment reversed lysosomal pathology in primary fibroblasts from 14 patients with eight different LSDs. HSP70 penetrated effectively into murine tissues including the CNS and inhibited glycosphingolipid accumulation in murine models of Fabry disease (Gla-/-), Sandhoff disease (Hexb-/-), and Niemann-Pick disease type C (Npc1-/-) and attenuated a wide spectrum of disease-associated neurological symptoms in Hexb-/- and Npc1-/- mice. Oral administration of arimoclomol, a small-molecule coinducer of HSPs that is currently in clinical trials for Niemann-Pick disease type C (NPC), recapitulated the effects of recombinant human HSP70, suggesting that heat shock protein-based therapies merit clinical evaluation for treating LSDs.",

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Kirkegaard, T, Gray, J, Priestman, DA, Wallom, KL, Atkins, J, Olsen, OD, Klein, A, Drndarski, S, Petersen, NHT, Ingemann, L, Smith, DA, Morris, L, Bornæs, C, Jørgensen, SH, Williams, I, Hinsby, A, Arenz, C, Begley, D, Jäättelä, M & Platt, FM 2016, 'Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses', Science Translational Medicine, vol. 8, no. 355, 355ra118. https://doi.org/10.1126/scitranslmed.aad9823

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AU - Kirkegaard, Thomas

AU - Gray, James

AU - Priestman, David A.

AU - Wallom, Kerri Lee

AU - Atkins, Jennifer

AU - Olsen, Ole Dines

AU - Klein, Alexander

AU - Drndarski, Svetlana

AU - Petersen, Nikolaj H T

AU - Ingemann, Linda

AU - Smith, David A.

AU - Morris, Lauren

AU - Bornæs, Claus

AU - Jørgensen, Signe Humle

AU - Williams, Ian

AU - Hinsby, Anders

AU - Arenz, Christoph

AU - Begley, David

AU - Jäättelä, Marja

AU - Platt, Frances M.

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N2 - Lysosomal storage diseases (LSDs) often manifest with severe systemic and central nervous system (CNS) symptoms. The existing treatment options are limited and have no or only modest efficacy against neurological manifestations of disease. We demonstrate that recombinant human heat shock protein 70 (HSP70) improves the binding of several sphingolipid-degrading enzymes to their essential cofactor bis(monoacyl)glycerophosphate in vitro. HSP70 treatment reversed lysosomal pathology in primary fibroblasts from 14 patients with eight different LSDs. HSP70 penetrated effectively into murine tissues including the CNS and inhibited glycosphingolipid accumulation in murine models of Fabry disease (Gla-/-), Sandhoff disease (Hexb-/-), and Niemann-Pick disease type C (Npc1-/-) and attenuated a wide spectrum of disease-associated neurological symptoms in Hexb-/- and Npc1-/- mice. Oral administration of arimoclomol, a small-molecule coinducer of HSPs that is currently in clinical trials for Niemann-Pick disease type C (NPC), recapitulated the effects of recombinant human HSP70, suggesting that heat shock protein-based therapies merit clinical evaluation for treating LSDs.

AB - Lysosomal storage diseases (LSDs) often manifest with severe systemic and central nervous system (CNS) symptoms. The existing treatment options are limited and have no or only modest efficacy against neurological manifestations of disease. We demonstrate that recombinant human heat shock protein 70 (HSP70) improves the binding of several sphingolipid-degrading enzymes to their essential cofactor bis(monoacyl)glycerophosphate in vitro. HSP70 treatment reversed lysosomal pathology in primary fibroblasts from 14 patients with eight different LSDs. HSP70 penetrated effectively into murine tissues including the CNS and inhibited glycosphingolipid accumulation in murine models of Fabry disease (Gla-/-), Sandhoff disease (Hexb-/-), and Niemann-Pick disease type C (Npc1-/-) and attenuated a wide spectrum of disease-associated neurological symptoms in Hexb-/- and Npc1-/- mice. Oral administration of arimoclomol, a small-molecule coinducer of HSPs that is currently in clinical trials for Niemann-Pick disease type C (NPC), recapitulated the effects of recombinant human HSP70, suggesting that heat shock protein-based therapies merit clinical evaluation for treating LSDs.

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DO - 10.1126/scitranslmed.aad9823

M3 - Article

AN - SCOPUS:84988869874

SN - 1946-6234

VL - 8

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 355

M1 - 355ra118

ER -

Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses

Abstract

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