Table 3 Summary of studies performed using iPSCs to model UCDs.
Donor Information | Experimental Design | |||||||
|---|---|---|---|---|---|---|---|---|
UCD subtype | Cell source | Genotype | Age | Sex | Clinical severity | Purpose of study | Differentiation | Control line used |
Ornithine transcarbamylase deficiency | PBMCs PBMCs Fibroblasts Fibroblasts | Deletion of 3 to 9 exons in OTC gene Hemizygote mutation (c.663 + 2 T > G); XXY c.386 G > A Exon 6, c.548 A > G [p.Tyr183Cys]; exon 3, c.274 C > T [p.Arg92*] | 4 days 3 days 9 months Neonatal; 6 years | M M M M, F | Hyperammonaemia Multiple organ failure Hyperammonaemia – liver transplantation Fatal neonatal hyperammonaemia; fatal acute liver failure | Generation of stem cell line from patient Generation of stem cell line from patient Assessment of genetic and phenotypic markers in both patient and corrected differentiated cells In vitro model of liver disease | Embryoid bodies Embryoid bodies Hepatocyte-like cells Hepatocyte-like cells | N/A55 N/A56 CRISPR/Cas9 corrected iPSCs53 Healthy donors57 |
Argininosuccinate synthetase deficiency (Citrullinemia type 1) | Fibroblasts PBMCs | p∼G390R (c.1168 G > A) Compound heterozygous: Exon 6, c.364-2 A > G, p. G259*; Exon 13, c.910 C > T, p. R304W | N/S 5 years | N/S F | Neonatal hyperammonaemia Neonatal hyperammonaemia | Generating and characterising the hepatic organoid (eHEPO) culture system Assessment of differentiated patient iPSCs, found partial recapitulation of patient phenotype | Hepatic organoids Hepatocyte-like cells | Healthy donors64 Healthy donors63 |
Argininosuccinate lyase deficiency | Fibroblasts | Compound heterozygous at exon 7 and 11 Compound heterozygous at exon 7 and 11 | N/S N/S | N/S N/S | N/S N/S | Assessment of effect of ASL loss on endothelial cells Assessment of loss of ASL on osteoblast differentiation | Endothelial cells Osteogenic | Healthy donors67 Helper-dependent adenovirus system corrected iPSCs68 |
Arginase deficiency | Fibroblasts | N/S | 1 F – 5 years Other lines N/S | 1 M, 2 F | Developmental delay, microcephaly, spasticity (1 F, 5 years), other lines N/S | Implement a CRISPR/Cas9-based strategy to genetically modify and restore arginase activity | Hepatocyte-like cells | Healthy donor69 |
Citrin or aspartate/glutamate carrier | Fibroblasts | Compound heterozygous (851del4; IVS16ins3kb) | 1-year old | M | Jaundice and liver failure | Assessment of differentiated patient-derived iPSCs – show that aberrant mitochondrial b-oxidation may give rise to fatty liver in citrin deficient patients | Hepatocyte-like cells | Healthy donor75 |
Carbamoyl phosphate synthetase 1 (CPS1) deficiency | Fibroblasts | E832X; D914H (c.4162-2 A > G); V204F | Neonatal | M, M, F | Neonatal hyperammonaemia | Assessment of differentiated patient-derived iPSCs in comparison to CRISPR/Cas9 corrected controls. | Hepatocyte-like cells | Human embryonic stem cells54 |
