Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses
| Autor: | Linda Ingemann, Frances M. Platt, James Gray, Thomas Kirkegaard, Signe Humle Jørgensen, Svetlana Drndarski, Ian D. Williams, David J. Begley, Christoph Arenz, Kerri-Lee Wallom, David Smith, Jennifer Atkins, David A. Priestman, Anders Mørkeberg Hinsby, Lauren Morris, Nikolaj H.T. Petersen, Claus Bornæs, Alexander Klein, Ole Dines Olsen, Marja Jäättelä |
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| Jazyk: | angličtina |
| Předmět: |
0301 basic medicine
Sandhoff disease Pharmacology Arimoclomol Biology Hydroxylamines Glycosphingolipids Sphingolipidoses 03 medical and health sciences chemistry.chemical_compound Niemann-Pick C1 Protein Heat shock protein medicine Animals Humans Tissue Distribution Heat-Shock Proteins Niemann–Pick disease type C Intracellular Signaling Peptides and Proteins Proteins nutritional and metabolic diseases Niemann-Pick Disease Type C General Medicine Fibroblasts medicine.disease Fabry disease Recombinant Proteins 3. Good health HEXB Disease Models Animal 030104 developmental biology chemistry Blood-Brain Barrier Bone Morphogenetic Proteins Disease Progression Fabry Disease Administration Intravenous Niemann–Pick disease Lysosomes Injections Intraperitoneal |
| Zdroj: | Science translational medicine. 8(355) |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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