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RNA Editing for the Treatment of Alpha-1 Antitrypsin Deficiency

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE267230 | GEO | 2026/01/12

REPOSITORIES: GEO

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Characterization of a new variant of SERPINA1 Gene Causing Alpha-1 Antitrypsin Deficiency

Project description:Alpha 1-Antitrypsin Deficiency (AATD) is a rare genetic disorder caused by mutations in the SERPINA1 gene, which encodes the Alpha 1-Antitrypsin (AAT) protein. Individuals carrying pathogenic SERPINA1 variants are predisposed to lung and liver damage. The most common AATD-associated SERPINA1 alleles are the S and Z alleles, though additional variants have been identified. This case report describes the discovery of a new SERPINA1 variant detected in two cities in southeastern France. This variant, named PiZmarseille, results from in cis combination of the PiZ allele and a rare variant known as PiZbristol. PiZmarseille has been associated with early-onset liver disease in childhood. To further investigate this new variant, we performed its molecular characterization, revealing that PiZmarseille shares the pathogenic properties of both the PiZ and PiZbristol variants. These properties include its retention in the endoplasmic reticulum as aggregates and its degradation through the autophagy and proteasome pathways. Additionally, we conducted proteomic profiling to explore the association of this mutant with liver disease. Our analysis revealed that the neutrophil degranulation pathway is particularly deregulated in PiZmarseille liver samples. Furthermore, when compared to other AAT genotypes, the proteomic profile of PiZmarseille most closely resembles that of the PiZ variant, rather than other SERPINA1 variants.

2025-12-08 | PXD060960 | Pride

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