ArticleJCI insight2020
Development of an RNAi therapeutic for alpha-1-antitrypsin liver disease.
Article in JCI insight, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
26 citing papers in PubMed, 56 citations in OpenAlex.
- Hypoxia Signaling and Non-Coding RNAs: Regulatory Networks and Therapeutic Implications in Breast Cancer.Current issues in molecular biology · 2026Review
- RNA editing for the treatment of alpha-1 antitrypsin deficiency.Nucleic acids research · 2026Article
- The Role of Alpha-1 Antitrypsin in the Pathophysiology and Treatment of Inflammatory Lung Diseases.Journal of inflammation research · 2026Review
- Alpha-1 antitrypsin deficiency: genetics, clinical manifestations, AI prognostics, and advanced imaging in liver disease.Annals of medicine and surgery (2012) · 2025Review
- Chaperone-mediated autophagy degrades SERPINA1Autophagy · 2025Article
- Fazirsiran for the treatment of alpha-1 antitrypsin deficiency-associated liver disease findings from the SEQUOIA phase 2 trial.Annals of medicine and surgery (2012) · 2025Article
- Clinical Utility of Non-Invasive Tests for Liver Fibrosis in People Living With Alpha-1 Antitrypsin Deficiency.Liver international : official journal of the International Association for the Study of the Liver · 2025Review
- Selection for somatic escape variants in SERPINA1 in the liver of patients with alpha-1 antitrypsin deficiency.Nature genetics · 2025Article
- Targeted animal models for preclinical assessment of cellular and gene therapies in pancreatic and liver diseases: regulatory and practical insights.Cytotherapy · 2025Review
- LncRNAs, RNA Therapeutics, and Emerging Technologies in Liver Pathobiology.Seminars in liver disease · 2025Review
- Nucleic Acid Therapeutics: Successes, Milestones, and Upcoming Innovation.Nucleic acid therapeutics · 2024Review
- Targeting the Liver with Nucleic Acid Therapeutics for the Treatment of Systemic Diseases of Liver Origin.Pharmacological reviews · 2023Review
- Innate immune regulations and various siRNA modalities.Drug delivery and translational research · 2023Review
- Targeted delivery of oligonucleotides using multivalent protein-carbohydrate interactions.Chemical Society reviews · 2023Review
- Oligonucleotide-Based Therapies for Chronic HBV Infection: A Primer on Biochemistry, Mechanisms and Antiviral Effects.Viruses · 2022Review
- Orphan drug development in alpha-1 antitypsin deficiency.Scientific reports · 2022Article
- Novel Gene-Correction-Based Therapeutic Modalities for Monogenic Liver Disorders.Bioengineering (Basel, Switzerland) · 2022Review
- Inhaled siRNA Formulations for Respiratory Diseases: From Basic Research to Clinical Application.Pharmaceutics · 2022Review
- The Progress and Promise of RNA Medicine─An Arsenal of Targeted Treatments.Journal of medicinal chemistry · 2022Review
- Evaluation of cytosine base editing and adenine base editing as a potential treatment for alpha-1 antitrypsin deficiency.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 2 countries.
Funding
Abstract
The autosomal codominant genetic disorder alpha-1 antitrypsin (AAT) deficiency (AATD) causes pulmonary and liver disease. Individuals homozygous for the mutant Z allele accumulate polymers of Z-AAT protein in hepatocytes, where AAT is primarily produced. This accumulation causes endoplasmic reticulum (ER) stress, oxidative stress, damage to mitochondria, and inflammation, leading to fibrosis, cirrhosis, and hepatocellular carcinoma. The magnitude of AAT reduction and duration of response from first-generation intravenously administered RNA interference (RNAi) therapeutic ARC-AAT and then with next-generation subcutaneously administered ARO-AAT were assessed by measuring AAT protein in serum of the PiZ transgenic mouse model and human volunteers. The impact of Z-AAT reduction by RNAi on liver disease phenotypes was evaluated in PiZ mice by measuring polymeric Z-AAT in the liver; expression of genes associated with fibrosis, autophagy, apoptosis, and redox regulation; inflammation; Z-AAT globule parameters; and tumor formation. Ultrastructure of the ER, mitochondria, and autophagosomes in hepatocytes was evaluated by electron microscopy. In mice, sustained RNAi treatment reduced hepatic Z-AAT polymer, restored ER and mitochondrial health, normalized expression of disease-associated genes, reduced inflammation, and prevented tumor formation. RNAi therapy holds promise for the treatment of patients with AATD-associated liver disease. ARO-AAT is currently in phase II/III clinical trials.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.