Niemann-Pick disease type C (NPC) is a rare prematurely fatal lysosomal lipid storage disease with limited therapeutic options. The prominent neuropathological hallmarks include hypomyelination and cerebellar atrophy. We previously demonstrated the efficacy of recombinant human heat shock protein 70 (rhHSP70) in preclinical models of the disease. It reduced glycosphingolipid levels in the central nervous system (CNS), improving cerebellar myelination and improved behavioural phenotypes in Npc1nih (Npc1−/−) mice. Furthermore, treatment with arimoclomol, a well-characterised HSP amplifier, attenuated lysosomal storage in NPC patient fibroblasts and improved neurological symptoms in Npc1−/− mice. Taken together, these findings prompted the investigation of the effects of HSP amplification on CNS myelination.
MethodsWe administered bimoclomol daily or rhHSP70 6 times per week to Npc1−/− (BALB/cNctr-Npc1m1N/J, also named Npc1nih) mice by intraperitoneal injection from P7 through P34 to investigate the impact on CNS myelination. The Src-kinase inhibitor saracatinib was administered with/without bimoclomol twice daily to explore the contribution of Fyn kinase to bimoclomol's effects.
FindingsTreatment with either bimoclomol or rhHSP70 improved myelination and increased the numbers of mature oligodendrocytes (OLs) as well as the ratio of active-to-inactive forms of phosphorylated Fyn kinase in the cerebellum of Npc1−/− mice. Additionally, treatment with bimoclomol preserved cerebellar weight, an effect that was abrogated when co-administered with saracatinib, an inhibitor of Fyn kinase. Bimoclomol-treated mice also exhibited increased numbers of immature OLs within the cortex.
InterpretationThese data increase our understanding of the mechanisms by which HSP70 regulates myelination and provide further support for the clinical development of HSP-amplifying therapies in the treatment of NPC.
FundingFunding for this study was provided by Orphazyme A/S (Copenhagen, Denmark) and a Pathfinder Award from The Wellcome Trust.
Keywordslysosomal storage diseases
Niemann-Pick disease type C
NPC
neurodegeneration
myelination
heat shock proteins
HSP70
cholesterol
glycosphingolipids
Fyn kinase
arimoclomol
bimoclomol
BALB/cNctr-Npc1m1N/J
Npc1nih
mice
© 2022 The Authors. Published by Elsevier B.V.
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