ArticleHuman molecular genetics2014
A genome-wide RNAi screen identifies potential drug targets in a C. elegans model of α1-antitrypsin deficiency.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 44 citations in OpenAlex.
- Caenorhabditis elegans for rare disease modeling and drug discovery: strategies and strengths.Disease models & mechanisms · 2021Review
- Impact of drug solvents onToxicology reports · 2021Article
- Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis.International journal of molecular sciences · 2020Article
- Alpha 1-Antitrypsin Deficiency: A Disorder of Proteostasis-Mediated Protein Folding and Trafficking Pathways.International journal of molecular sciences · 2020Review
- Digging deeper: methodologies for high-content phenotyping in Caenorhabditis elegans.Lab animal · 2019Review
- An analog of glibenclamide selectively enhances autophagic degradation of misfolded α1-antitrypsin Z.PloS one · 2019Article
- Article
- Combined flow cytometry and high-throughput image analysis for the study of essential genes in Caenorhabditis elegans.BMC biology · 2018Article
- Whole-Transcriptome Sequencing: a Powerful Tool for Vascular Tissue Engineering and Endothelial Mechanobiology.High-throughput · 2018Review
- An enhanced C. elegans based platform for toxicity assessment.Scientific reports · 2017Article
- A Phenotype-Based RNAi Screening for Ras-ERK/MAPK Signaling-Associated Stem Cell Regulators in C. elegans.Methods in molecular biology (Clifton, N.J.) · 2017Article
- The struggle by Caenorhabditis elegans to maintain proteostasis during aging and disease.Biology direct · 2016Review
- A Perspective on Implementing a Quantitative Systems Pharmacology Platform for Drug Discovery and the Advancement of Personalized Medicine.Journal of biomolecular screening · 2016Article
- STITCH 5: augmenting protein-chemical interaction networks with tissue and affinity data.Nucleic acids research · 2016Article
- Induced Pluripotent Stem Cell Models to Enable In Vitro Models for Screening in the Central Nervous System.Stem cells and development · 2015Review
- Diabetic silkworms for evaluation of therapeutically effective drugs against type II diabetes.Scientific reports · 2015Article
- The aggregation-prone intracellular serpin SRP-2 fails to transit the ER in Caenorhabditis elegans.Genetics · 2015Article
- Deficient and Null Variants of SERPINA1 Are Proteotoxic in a Caenorhabditis elegans Model of α1-Antitrypsin Deficiency.PloS one · 2015Article
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
α1-Antitrypsin deficiency (ATD) is a common genetic disorder that can lead to end-stage liver and lung disease. Although liver transplantation remains the only therapy currently available, manipulation of the proteostasis network (PN) by small molecule therapeutics offers great promise. To accelerate the drug-discovery process for this disease, we first developed a semi-automated high-throughput/content-genome-wide RNAi screen to identify PN modifiers affecting the accumulation of the α1-antitrypsin Z mutant (ATZ) in a Caenorhabditis elegans model of ATD. We identified 104 PN modifiers, and these genes were used in a computational strategy to identify human ortholog-ligand pairs. Based on rigorous selection criteria, we identified four FDA-approved drugs directed against four different PN targets that decreased the accumulation of ATZ in C. elegans. We also tested one of the compounds in a mammalian cell line with similar results. This methodology also proved useful in confirming drug targets in vivo, and predicting the success of combination therapy. We propose that small animal models of genetic disorders combined with genome-wide RNAi screening and computational methods can be used to rapidly, economically and strategically prime the preclinical discovery pipeline for rare and neglected diseases with limited therapeutic options.
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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.