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 journalArticlepeer-review

114 Citations (Scopus)


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 languageEnglish
Article number355ra118
JournalScience Translational Medicine
Issue number355
Publication statusPublished - 7 Sept 2016


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