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Targeting protein homeostasis in sporadic inclusion body myositis.

Abstract：

:Sporadic inclusion body myositis (sIBM) is the commonest severe myopathy in patients more than 50 years of age. Previous therapeutic trials have targeted the inflammatory features of sIBM but all have failed. Because protein dyshomeostasis may also play a role in sIBM, we tested the effects of targeting this feature of the disease. Using rat myoblast cultures, we found that up-regulation of the heat shock response with arimoclomol reduced key pathological markers of sIBM in vitro. Furthermore, in mutant valosin-containing protein (VCP) mice, which develop an inclusion body myopathy, treatment with arimoclomol ameliorated disease pathology and improved muscle function. We therefore evaluated arimoclomol in an investigator-led, randomized, double-blind, placebo-controlled, proof-of-concept trial in sIBM patients and showed that arimoclomol was safe and well tolerated. Although arimoclomol improved some IBM-like pathology in the mutant VCP mouse, we did not see statistically significant evidence of efficacy in the proof-of-concept patient trial.

journal_name

Sci Transl Med

journal_title

Science translational medicine

authors

Ahmed M,Machado PM,Miller A,Spicer C,Herbelin L,He J,Noel J,Wang Y,McVey AL,Pasnoor M,Gallagher P,Statland J,Lu CH,Kalmar B,Brady S,Sethi H,Samandouras G,Parton M,Holton JL,Weston A,Collinson L,Taylor JP,Schia

doi

10.1126/scitranslmed.aad4583

subject

Has Abstract

pub_date

2016-03-23 00:00:00

pages

331ra41

issue

331

eissn

1946-6234

issn

1946-6242

pii

8/331/331ra41

journal_volume

8

pub_type

杂志文章

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