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

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. and Platt, F.M. 2016. Heat shock protein–based therapy as a potential candidate for treating the sphingolipidoses. Science Translational Medicine. 8 (355), p. 355ra188 355ra188. https://doi.org/10.1126/scitranslmed.aad9823

TitleHeat shock protein–based therapy as a potential candidate for treating the sphingolipidoses
TypeJournal article
AuthorsKirkegaard, 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.
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.

Article number355ra188
JournalScience Translational Medicine
Journal citation8 (355), p. 355ra188
ISSN1946-6234
Year2016
PublisherAmerican Association for the Advancement of Science
Digital Object Identifier (DOI)https://doi.org/10.1126/scitranslmed.aad9823
PubMed ID27605553
Web address (URL)https://stm.sciencemag.org/content/8/355/355ra118.short
Publication dates
Published07 Sep 2016

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