Liver
Alpha-1 antitrypsin deficiency
Optimized bioassays for the preclinical screening of small molecules, siRNA and oligo therapeutic candidates and base editing approaches
A1ATD drug screening platform
DefiniGEN provide iPSC-derived disease model hepatocytes of Alpha-1 antitrypsin (A1AT) deficiency; associated with the PiZ variant of the Alpha-1 antitrypsin, caused by a (G>A) point mutation at codon 342 (Glu342Lys) in exon 5 of the SERPINA1 gene. Using CRISPR gene editing we successfully introduced the PiZ mutation into our in-house iPSC line, differentiated to hepatocytes using our Opti-Diff process and screened for key hepatic and disease markers using high content imaging.
The resulting cells were shown to have a strong hepatic phenotype and to display increase intracellular expression of polymeric A1AT which is characteristic of Alpha-1 antitrypsin deficiency. Subsequently we assessed the suitability of these cells for screening of small molecule and RNA-based therapies by transferring them to multiwell plates and treating with reference compounds (in particular Carbamazipine) or RNA-modulating molecules.
The cells were able to demonstrate dose-dependent restoration of function across a broad range of drug concentrations, these data confirm both sensitivity and specificity of response to treatment and therefore this disease model is highly applicable to candidate drug screening in A1ATD.
Compound response
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