Updates in the Management of Alpha-1 Antitrypsin Deficiency Lung Disease

Goel, Khushboo; Strange, Charlie; Sandhaus, Robert A.; Petrache, Irina; Serban, Karina A.

doi:10.17925/usprd.2021.6.1.26

US Respiratory &Amp; Pulmonary Diseases

2021

DOI: 10.17925/usprd.2021.6.1.26

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Updates in the Management of Alpha-1 Antitrypsin Deficiency Lung Disease

Khushboo Goel¹,

Charlie Strange²,

Robert A. Sandhaus³

et al.

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2022

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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

Zhukovsky¹,

Silvano²,

Filloux³

et al. 2022

IJMS

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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.

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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

Zhukovsky¹,

Silvano²,

Filloux³

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

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Updates in the Management of Alpha-1 Antitrypsin Deficiency Lung Disease

Cited by 1 publication

References 68 publications

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

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

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