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Preliminary RNA-seq data obtained from H1975 and H661 cells exposed to AAT protein

ABSTRACT: Although the classical function of AAT is to inhibit neutrophil proteases, there is evidence that the role of AAT in inflammation is multifaceted. AAT possesses anti-inflammatory activity against immune cells, affects leukotriene B4, TNF-α, IL-8, IFN-γ and IL-1β production and expresses potent anti-apoptotic properties. In addition, AAT has been shown to inhibit the activity of natural killer cells against tumor cells, which indicates that AAT may play multiple functions during cancer development. Therefore, in a situation of occurring cancer cells higher AAT levels may favor microenvironment towards malignant progression. High expression of SERPINA1 gene encoding acute phase protein, α1-antitrypsin (AAT), is associated with poor prognosis in various tumors. Here we examined the significance of SERPINA1 and AAT protein in non-small-cell lung cancer (NSCLC) patients and NSCLC cell lines.

ORGANISM(S): Homo sapiens

PROVIDER: GSE135138 | GEO | 2019/07/31

REPOSITORIES: GEO

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RNA Editing for the Treatment of Alpha-1 Antitrypsin Deficiency

Project description:Alpha-1 antitrypsin deficiency (AATD) is both a gain- and loss-of-function disease that impacts the liver and lung.1 Most severe cases result from a homozygous missense mutation in the SERPINA1 gene (Z mutation). While current therapies and those in development may ameliorate lung or liver disease, few are designed to address both.1 We have developed SERPINA1-994, a N-Acetylgalactosamine-conjugated chemically modified oligonucleotide that elicits adenine-to-inosine RNA editing using endogenous adenosine deaminases acting on RNA enzymes, to correct SERPINA1 Z transcripts. We show that SERPINA1-994 edits 50% of the Z transcript in hepatocytes of NSG-PiZ mice, which increases total serum AAT levels and induces the production of wild-type protein. SERPINA1-994 addresses loss of AAT function in lung by increasing the neutrophil elastase inhibition capacity of mouse serum and gain-of-function in liver by decreasing protein aggregation, decreasing inflammation and correcting gene expression patterns. SERPINA1-994 relies on a clinically proven delivery technology and directs highly specific RNA rather than DNA editing, so there is no risk for permanent off-target effects. Overall, these data suggest that SERPINA1-994 changes a ZZ homozygous state, which is associated with a high risk for AATD, to a low-risk MZ-like phenotype.

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2025-12-08 | PXD060960 | Pride

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| PRJNA694109 | ENA

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