CRISPR Correction of the Finnish Ornithine Delta-aminotransferase Mutation Restores Metabolic Homeostasis in IPSC from Patients with Gyrate Atrophy

Overview

Journal Mol Genet Metab Rep

Specialty Endocrinology

Date 2022 Jul 5

PMID 35782600

Authors

Rocio Maldonado

Sami Jalil

Timo Keskinen

Anni I Nieminen

Mervi E Hyvonen

Risto Lapatto

Kirmo Wartiovaara

Affiliations

Soon will be listed here.

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 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 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.

Citing Articles

Novel Insights Into Gyrate Atrophy of the Choroid and Retina (GACR): A Cohort Study.

Balfoort B, Van den Broeck F, Boon C, Brouwers M, Diederen R, Dhillon P J Inherit Metab Dis. 2025; 48(1):e12842.

PMID: 39761806 PMC: 11703598. DOI: 10.1002/jimd.12842.

Induced Pluripotent Stem Cells and CRISPR-Cas9 Innovations for Treating Alpha-1 Antitrypsin Deficiency and Glycogen Storage Diseases.

Walsh C, Jin S Cells. 2024; 13(12.

PMID: 38920680 PMC: 11201389. DOI: 10.3390/cells13121052.

Ancestral allele of DNA polymerase gamma modifies antiviral tolerance.

Kang Y, Hepojoki J, Sartori Maldonado R, Mito T, Terzioglu M, Manninen T Nature. 2024; 628(8009):844-853.

PMID: 38570685 PMC: 11041766. DOI: 10.1038/s41586-024-07260-z.

References

Shih V, Mandell R, Berson E . Pyridoxine effects on ornithine ketoacid transaminase activity in fibroblasts from carriers of two forms of gyrate atrophy of the choroid and retina. Am J Hum Genet. 1988; 43(6):929-33. PMC: 1715599. View

Sipila I . Inhibition of arginine-glycine amidinotransferase by ornithine. A possible mechanism for the muscular and chorioretinal atrophies in gyrate atrophy of the choroid and retina with hyperornithinemia. Biochim Biophys Acta. 1980; 613(1):79-84. DOI: 10.1016/0005-2744(80)90194-1. View

Wu W, Tsai Y, Justus S, Lee T, Zhang L, Lin C . CRISPR Repair Reveals Causative Mutation in a Preclinical Model of Retinitis Pigmentosa. Mol Ther. 2016; 24(8):1388-94. PMC: 5023380. DOI: 10.1038/mt.2016.107. View

Kaiser-Kupfer M, Caruso R, Valle D, Reed G . Use of an arginine-restricted diet to slow progression of visual loss in patients with gyrate atrophy. Arch Ophthalmol. 2004; 122(7):982-4. DOI: 10.1001/archopht.122.7.982. View

Mitchell G, Brody L, Looney J, Steel G, Suchanek M, Dowling C . An initiator codon mutation in ornithine-delta-aminotransferase causing gyrate atrophy of the choroid and retina. J Clin Invest. 1988; 81(2):630-3. PMC: 329615. DOI: 10.1172/JCI113365. View

Suh S, Choi E, Leinonen H, Foik A, Newby G, Yeh W . Restoration of visual function in adult mice with an inherited retinal disease via adenine base editing. Nat Biomed Eng. 2020; 5(2):169-178. PMC: 7885272. DOI: 10.1038/s41551-020-00632-6. View

Concordet J, Haeussler M . CRISPOR: intuitive guide selection for CRISPR/Cas9 genome editing experiments and screens. Nucleic Acids Res. 2018; 46(W1):W242-W245. PMC: 6030908. DOI: 10.1093/nar/gky354. View

Sipila I, Rapola J, Simell O, Vannas A . Supplementary creatine as a treatment for gyrate atrophy of the choroid and retina. N Engl J Med. 1981; 304(15):867-70. DOI: 10.1056/NEJM198104093041503. View

Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S . A more efficient method to generate integration-free human iPS cells. Nat Methods. 2011; 8(5):409-12. DOI: 10.1038/nmeth.1591. View

10.

Valle D, Walser M, Brusilow S . Gyrate atrophy of the choroid and retina: amino acid metabolism and correction of hyperornithinemia with an arginine-deficient diet. J Clin Invest. 1980; 65(2):371-8. PMC: 371375. DOI: 10.1172/JCI109680. View

11.

Weltner J, Balboa D, Katayama S, Bespalov M, Krjutskov K, Jouhilahti E . Human pluripotent reprogramming with CRISPR activators. Nat Commun. 2018; 9(1):2643. PMC: 6035213. DOI: 10.1038/s41467-018-05067-x. View

12.

Wang T, Steel G, Milam A, Valle D . Correction of ornithine accumulation prevents retinal degeneration in a mouse model of gyrate atrophy of the choroid and retina. Proc Natl Acad Sci U S A. 2000; 97(3):1224-9. PMC: 15576. DOI: 10.1073/pnas.97.3.1224. View

13.

Sipila I, Simell O, Rapola J, Sainio K, TUUTERI L . Gyrate atrophy of the choroid and retina with hyperornithinemia: tubular aggregates and type 2 fiber atrophy in muscle. Neurology. 1979; 29(7):996-1005. DOI: 10.1212/wnl.29.7.996. View

14.

Peltola K, Heinonen O, Nanto-Salonen K, Pulkki K, Simell O . Oral lysine feeding in gyrate atrophy with hyperornithinaemia--a pilot study. J Inherit Metab Dis. 2000; 23(4):305-7. DOI: 10.1023/a:1005638004530. View

15.

Weleber R, Kurz D, Trzupek K . Treatment of retinal and choroidal degenerations and dystrophies: current status and prospects for gene-based therapy. Ophthalmol Clin North Am. 2004; 16(4):583-93, vii. DOI: 10.1016/s0896-1549(03)00072-5. View

16.

Caruso R, Valle D . Gyrate atrophy of the choroid and retina. Long-term reduction of ornithine slows retinal degeneration. Arch Ophthalmol. 1991; 109(11):1539-48. DOI: 10.1001/archopht.1991.01080110075039. View

17.

Brody L, Mitchell G, Obie C, Michaud J, Steel G, Fontaine G . Ornithine delta-aminotransferase mutations in gyrate atrophy. Allelic heterogeneity and functional consequences. J Biol Chem. 1992; 267(5):3302-7. View

18.

Montioli R, Bellezza I, Desbats M, Borri Voltattorni C, Salviati L, Cellini B . Deficit of human ornithine aminotransferase in gyrate atrophy: Molecular, cellular, and clinical aspects. Biochim Biophys Acta Proteins Proteom. 2020; 1869(1):140555. DOI: 10.1016/j.bbapap.2020.140555. View

19.

Sipila I, Simell O, Arjomaa P . Gyrate atrophy of the choroid and retina with hyperornithinemia. Deficient formation of guanidinoacetic acid from arginine. J Clin Invest. 1980; 66(4):684-7. PMC: 371642. DOI: 10.1172/JCI109905. View

20.

Wang T, Milam A, Steel G, Valle D . A mouse model of gyrate atrophy of the choroid and retina. Early retinal pigment epithelium damage and progressive retinal degeneration. J Clin Invest. 1996; 97(12):2753-62. PMC: 507368. DOI: 10.1172/JCI118730. View