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

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.

• Authors: 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
• Journal: Science translational medicine (Sci Transl Med) Vol. 8 Issue 355 Pg. 355ra118 (09 07 2016) ISSN: 1946-6242 [Electronic] United States
• PMID: 27605553 (Publication Type: Journal Article)
• Copyright: Copyright © 2016, American Association for the Advancement of Science.

Chemical References

• Bone Morphogenetic Proteins
• Glycosphingolipids
• Heat-Shock Proteins
• Hydroxylamines
• Intracellular Signaling Peptides and Proteins
• Niemann-Pick C1 Protein
• Npc1 protein, mouse
• Proteins
• Recombinant Proteins
• arimoclomol

Topics

• Administration, Intravenous
• Animals
• Blood-Brain Barrier (drug effects, pathology)
• Bone Morphogenetic Proteins (metabolism)
• Disease Models, Animal
• Disease Progression
• Fabry Disease (drug therapy, pathology)
• Fibroblasts (drug effects, metabolism, pathology)
• Glycosphingolipids (metabolism)
• Heat-Shock Proteins (pharmacology, therapeutic use)
• Humans
• Hydroxylamines (pharmacology, therapeutic use)
• Injections, Intraperitoneal
• Intracellular Signaling Peptides and Proteins
• Lysosomes (drug effects, pathology)
• Niemann-Pick C1 Protein
• Niemann-Pick Disease, Type C (drug therapy)
• Proteins (metabolism)
• Recombinant Proteins (pharmacokinetics, pharmacology, therapeutic use)
• Sphingolipidoses (drug therapy, pathology)
• Tissue Distribution