A genome-wide RNAi screen identifies potential drug targets in a C. elegans model of α1-antitrypsin deficiency.
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.
Department of Pediatrics, Cell Biology and.
Linda P
LP
O'Reilly
Department of Pediatrics, Cell Biology and.
Olivia S
OS
Long
Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC and Magee-Womens Hospital Research Institute, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.
Murat C
MC
Cobanoglu
Department of Pediatrics, Cell Biology and.
Joshua A
JA
Benson
Department of Pediatrics, Cell Biology and.
Cliff J
CJ
Luke
Department of Pediatrics, Cell Biology and.
Mark T
MT
Miedel
Department of Pediatrics, Cell Biology and.
Pamela
P
Hale
Department of Pediatrics, Cell Biology and.
David H
DH
Perlmutter
Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC and Magee-Womens Hospital Research Institute, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.
Ivet
I
Bahar
Department of Pediatrics, Cell Biology and.
Gary A
GA
Silverman
Department of Pediatrics, Cell Biology and paksc@upmc.edu.
Stephen C
SC
Pak
D000818:Animals; D017173:Caenorhabditis elegans; D019295:Computational Biology; D004195:Disease Models, Animal; D055808:Drug Discovery; D055106:Genome-Wide Association Study; D023281:Genomics; D057166:High-Throughput Screening Assays; D006801:Humans; D009154:Mutation; D011485:Protein Binding; D057165:Proteostasis Deficiencies / Q000235:genetics; D034622:RNA Interference; D015203:Reproducibility of Results; D000515:alpha 1-Antitrypsin / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000188:drug therapy / Q000235:genetics*
D000515:alpha 1-Antitrypsin