Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses.
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.
Orphazyme ApS, Copenhagen, Denmark. tkj@orphazyme.com.
Thomas
T
Kirkegaard
Department of Pharmacology, University of Oxford, Oxford, U.K.
James
J
Gray
Department of Pharmacology, University of Oxford, Oxford, U.K.
David A
DA
Priestman
Department of Pharmacology, University of Oxford, Oxford, U.K.
Kerri-Lee
KL
Wallom
Department of Pharmacology, University of Oxford, Oxford, U.K.
Jennifer
J
Atkins
Orphazyme ApS, Copenhagen, Denmark. Cell Death and Metabolism Unit, Center for Autophagy, Recycling, and Metabolism, Danish Cancer Society Research Center, Copenhagen, Denmark.
Ole Dines
OD
Olsen
Institut für Chemie der Humboldt-Universität zu Berlin, Berlin, Germany.
Alexander
A
Klein
Institute of Pharmaceutical Science, King's College London, London, U.K.
Svetlana
S
Drndarski
Orphazyme ApS, Copenhagen, Denmark.
Nikolaj H T
NH
Petersen
Orphazyme ApS, Copenhagen, Denmark.
Linda
L
Ingemann
Department of Pharmacology, University of Oxford, Oxford, U.K.
David A
DA
Smith
Department of Pharmacology, University of Oxford, Oxford, U.K.
Lauren
L
Morris
Orphazyme ApS, Copenhagen, Denmark.
Claus
C
Bornæs
Orphazyme ApS, Copenhagen, Denmark.
Signe Humle
SH
Jørgensen
Department of Pharmacology, University of Oxford, Oxford, U.K.
Ian
I
Williams
Orphazyme ApS, Copenhagen, Denmark.
Anders
A
Hinsby
Institut für Chemie der Humboldt-Universität zu Berlin, Berlin, Germany.
Christoph
C
Arenz
Institute of Pharmaceutical Science, King's College London, London, U.K.
David
D
Begley
Cell Death and Metabolism Unit, Center for Autophagy, Recycling, and Metabolism, Danish Cancer Society Research Center, Copenhagen, Denmark.
Marja
M
Jäättelä
Department of Pharmacology, University of Oxford, Oxford, U.K.
Frances M
FM
Platt
D061605:Administration, Intravenous; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D000795:Fabry Disease / Q000188:drug therapy / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006028:Glycosphingolipids / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000187:drug effects / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy; D011506:Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D013106:Sphingolipidoses / Q000188:drug therapy* / Q000473:pathology; D014018:Tissue Distribution
D019485:Bone Morphogenetic Proteins; D006028:Glycosphingolipids; D006360:Heat-Shock Proteins; D006898:Hydroxylamines; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D011994:Recombinant Proteins; C486387:arimoclomol