RNA-seq of human cell line HepG2 edited with CRISPR and treated with splice-switching oligo inhibiting a pseudoexon in PCCA against control SSO and control HepG2 cells. RNA-seq of human cell line HepG2 edited with CRISPR and treated with splice-switching oligo inhibiting a pseudoexon in PCCA against control SSO and control HepG2 cells

Cellular models of propionic acidemia were generated using HepG2 cells that were edited by CRISPR gene editing to introduce the pathogenic PCCA c.1285-1416A>G variant associated with propionic acidemia, and a 7 bp deletion of a predicted hnRNP A1 binding motif (c.1285-1411delTAGAACA), which causes complete and partial activation of an 84 bp pseudoexon from intron 14 in the PCCA gene, respectively. Treatment by transfection of splice-switching antisense oligonucleotides (SSO) to block inclusion of the PCCA pseudoexon in mRNA, was used to investigate this as a potential therapeutic strategy.