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

被引：120

作者：

Kirkegaard, Thomas ^{[1
]}

Gray, James ^{[2
]}

Priestman, David A. ^{[2
]}

Wallom, Kerri-Lee ^{[2
]}

Atkins, Jennifer ^{[2
]}

Olsen, Ole Dines ^{[1
,3
]}

Klein, Alexander ^{[4
]}

Drndarski, Svetlana ^{[5
]}

Petersen, Nikolaj H. T. ^{[1
]}

Ingemann, Linda ^{[1
]}

Smith, David A. ^{[2
]}

Morris, Lauren ^{[2
]}

Bornaes, Claus ^{[1
]}

Jorgensen, Signe Humle ^{[1
]}

Williams, Ian ^{[2
]}

Hinsby, Anders ^{[1
]}

Arenz, Christoph ^{[4
]}

Begley, David ^{[5
]}

Jaattela, Marja ^{[3
]}

Platt, Frances M. ^{[2
]}

机构：

[1] Orphazyme ApS, Copenhagen, Denmark

[2] Univ Oxford, Dept Pharmacol, Oxford, England

[3] Danish Canc Soc Res Ctr, Cell Death & Metab Unit, Ctr Autophagy Recycling & Metab, Copenhagen, Denmark

[4] Humboldt Univ, Inst Chem, Berlin, Germany

[5] Kings Coll London, Inst Pharmaceut Sci, London, England

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2016年 / 8卷 / 355期

基金：

英国医学研究理事会; 欧洲研究理事会; 新加坡国家研究基金会; 英国惠康基金;

关键词：

DISEASE TYPE-C; RETICULUM-ASSOCIATED DEGRADATION; LYSOSOMAL STORAGE DISORDERS; MOUSE MODEL; ALPHA-GALACTOSIDASE; GLUCOCEREBROSIDASE ACTIVITY; HUMAN HEAT-SHOCK-PROTEIN-70; CHOLESTEROL ACCUMULATION; ACTIVATOR PROTEINS; GAUCHER-DISEASE;

D O I：

10.1126/scitranslmed.aad9823

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：16

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