SUMMARY:
hAAT might help with the progression of CMT1A.
TITLE:
Alpha-1 Antitrypsin Reduces Disease Progression in a Mouse Model of Charcot-Marie-Tooth Type 1A: A Role for Decreased Inflammation and ADAM-17 Inhibition
DESCRIPTION:
Charcot-Marie-Tooth disease type 1 (CMT1A) is a hereditary peripheral neuropathy for which there is no available therapy. Alpha-1 antitrypsin (AAT) is an abundant serine protease inhibitor with anti-inflammatory and immunomodulating properties. Here, we tested whether treatment with human AAT (hAAT) would have a therapeutic effect on CMT1A in a PMP22 transgenic mouse model. Our results show that hAAT significantly improved compound muscle action potential and histopathological features and…
CONTENT:
Int J Mol Sci. 2022 Jul 3;23(13):7405. doi: 10.3390/ijms23137405.
ABSTRACT
Charcot-Marie-Tooth disease type 1 (CMT1A) is a hereditary peripheral neuropathy for which there is no available therapy. Alpha-1 antitrypsin (AAT) is an abundant serine protease inhibitor with anti-inflammatory and immunomodulating properties. Here, we tested whether treatment with human AAT (hAAT) would have a therapeutic effect on CMT1A in a PMP22 transgenic mouse model. Our results show that hAAT significantly improved compound muscle action potential and histopathological features and decreased circulating IL-6 in CMT1A mice. We also investigated some of the possible underlying mechanisms in vitro. We confirmed that hAAT inhibits ADAM-17, a protease that has been implicated in blocking myelination. Furthermore, both hAAT and recombinant human AAT (rhAAT) were able to attenuate the activation of a macrophage/microglia cell line, markedly decreasing the activation of the MHC class II promoter and the expression of pro-inflammatory genes such as IL-1β and the endoplasmic reticulum (ER) stress marker ATF3 . Taken together, our results demonstrate for the first time that hAAT is able to reduce the progression of CMT1A, possibly by dampening inflammation and by regulating ADAM-17. Given the already well-established safety profile of hAAT, specifically in AAT deficiency disease (AATD), we suggest that the findings of our study should be promptly investigated in CMT1A patients.
PMID:35806409 | DOI:10.3390/ijms23137405
SOURCE:
International journal of molecular sciences
TAGS:
hAAT
CATEGORY:
Research
SUBCATEGORY:
n/a
DATE – PUBLISHED:
2022-07-04T03:12:22Z
DATE – DOI: 2022-07-04T03:12:22Z
DATE – PUBMED: 2022 Jul 3
DATE OUTPUT MATCHED: True
DATE – ADDED:
Sat, 09 Jul 2022 06:00:00 -0400
DATE – RETRIEVED:
07/09/22 09:45AM
2022-07-09T09:45:43-04:00
FEATURED IMAGE:
Media Uploaded (image/png)
IDENTIFIER:
pmid:35806409,doi:10.3390/ijms23137405
PUBMED ID:
pubmed:35806409
DOI:
10.3390/ijms23137405
LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/35806409/
LINK – DOI:
https://doi.org/10.3390/ijms23137405
LINK – PUBLISHER:
https://www.mdpi.com/1422-0067/23/13/7405
REFERENCES:
CMT Treatment Report, Urgent Research, 2022-07-09T09:45:43-04:00, https://www.cmttreatmentreport.com.
