CRISPR correction of the Finnish ornithine delta-aminotransferase mutation restores metabolic homeostasis in iPSC from patients with gyrate atrophy

Rocio Maldonado; Sami Jalil; Timo Keskinen; Anni I Nieminen; Mervi E Hyvönen; Risto Lapatto; Kirmo Wartiovaara

doi:10.1016/j.ymgmr.2022.100863

CRISPR correction of the Finnish ornithine delta-aminotransferase mutation restores metabolic homeostasis in iPSC from patients with gyrate atrophy

Mol Genet Metab Rep. 2022 Apr 1:31:100863. doi: 10.1016/j.ymgmr.2022.100863. eCollection 2022 Jun.

Authors

Rocio Maldonado¹, Sami Jalil¹, Timo Keskinen¹, Anni I Nieminen², Mervi E Hyvönen^{1

3}, Risto Lapatto^{1

3}, Kirmo Wartiovaara^{1

4}

Affiliations

¹ Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
² Metabolomics Unit, Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
³ Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁴ Clinical Genetics, Helsinki University Hospital, Helsinki, Finland.

Abstract

Hyperornithinemia with gyrate atrophy of the choroid and retina (HOGA) is a severe recessive inherited disease, causing muscular degeneration and retinochoroidal atrophy that progresses to blindness. HOGA arises from mutations in the ornithine aminotransferase (OAT) gene, and nearly one-third of the known patients worldwide are homozygous for the Finnish founder mutation OAT c.1205 T > C p.(Leu402Pro). We have corrected this loss-of-function OAT mutation in patient-derived induced pluripotent stem cells (iPSCs) using CRISPR/Cas9. The correction restored OAT expression in stem cells and normalized the elevated ornithine levels in cell lysates and cell media. These results show an efficient recovery of OAT function in iPSC, encouraging the possibility of autologous cell therapy for the HOGA disease.

Keywords: CRISPR/Cas9; HOGA OAT; gene editing; gyrate atrophy.