SUMMARY:
cemdomespib therapy improved CMTX1-linked neuropathy in an Hsp70-dependent but a c-jun-independent manner and without regard to the nature of the underlying Cx32 mutation.
TITLE:
Pharmacologic Targeting of the C-Terminus of Heat Shock Protein 90 Improves Neuromuscular Function in Animal Models of Charcot Marie Tooth X1 Disease
DESCRIPTION:
Charcot-Marie-Tooth X1 (CMTX1) disease is an inherited peripheral neuropathy that arises from loss-of-function mutations in the protein connexin 32 (Cx32). CMTX1 currently lacks a pharmacologic approach toward disease management, and we have previously shown that modulating the expression of molecular chaperones using novologue therapy may provide a viable disease-modifying approach to treat metabolic and demyelinating neuropathies. Cemdomespib is an orally bioavailable novologue that manifests…
CONTENT:
ACS Pharmacol Transl Sci. 2023 Jan 20;6(2):306-319. doi: 10.1021/acsptsci.2c00223. eCollection 2023 Feb 10.
ABSTRACT
Charcot-Marie-Tooth X1 (CMTX1) disease is an inherited peripheral neuropathy that arises from loss-of-function mutations in the protein connexin 32 (Cx32). CMTX1 currently lacks a pharmacologic approach toward disease management, and we have previously shown that modulating the expression of molecular chaperones using novologue therapy may provide a viable disease-modifying approach to treat metabolic and demyelinating neuropathies. Cemdomespib is an orally bioavailable novologue that manifests neuroprotective activity by modulating the expression of heat shock protein 70 (Hsp70). We examined if 1 to 5 months of daily cemdomespib therapy may improve neuropathic symptoms in three mouse models of CMTX1 (Cx32 deficient (Cx32def), T55I-Cx32def, and R75W-Cx32 mice). Daily drug therapy significantly improved motor nerve conduction velocity (MNCV) and grip strength in all three models, but the compound muscle action potential was only improved in Cx32def mice. Drug efficacy required Hsp70 as improvements in MNCV, and the grip strength was abrogated in Cx32def × Hsp70 knockout mice. Five months of novologue therapy was associated with improved neuromuscular junction morphology, femoral motor nerve myelination, reduction in foamy macrophages, and a decrease in Schwann cell c-jun levels. To determine if c-jun may be downstream of Hsp70 and necessary for drug efficacy, c-jun expression was specifically deleted in Schwann cells of Cx32def mice. While the deletion of c-jun worsened the neuropathy, cemdomespib therapy remained effective in improving MNCV and grip strength. Our data show that cemdomespib therapy improves CMTX1-linked neuropathy in an Hsp70-dependent but a c-jun-independent manner and without regard to the nature of the underlying Cx32 mutation.
PMID:36798471 | PMC:PMC9926526 | DOI:10.1021/acsptsci.2c00223
SOURCE:
ACS pharmacology & translational science
TAGS:
cemdomespib
CATEGORY:
Research
SUBCATEGORY:
n/a
DATE – PUBLISHED:
2023-01-20T13:19:21Z
DATE – DOI: 2023-01-20T13:19:21Z
DATE – PUBMED: 2023 Jan 20
DATE OUTPUT MATCHED: True
DATE – ADDED:
Fri, 17 Feb 2023 06:00:00 -0500
DATE – RETRIEVED:
02/17/23 07:07AM
2023-02-17T07:07:05-05:00
FEATURED IMAGE:
Media Uploaded (image/png)
IDENTIFIER:
pmid:36798471,pmc:PMC9926526,doi:10.1021/acsptsci.2c00223
PUBMED ID:
pubmed:36798471
DOI:
10.1021/acsptsci.2c00223
LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36798471/
LINK – DOI:
https://doi.org/10.1021/acsptsci.2c00223
LINK – PUBLISHER:
https://pubs.acs.org/doi/10.1021/acsptsci.2c00223
REFERENCES:
CMT Treatment Report, Urgent Research, 2023-02-17T07:07:05-05:00, https://www.cmttreatmentreport.com.
