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Sci Rep. 2019 Mar 18;9(1):4695. doi: 10.1038/s41598-019-41056-w.

Function and Immunogenicity of Gene-corrected iPSC-derived Hepatocyte-Like Cells in Restoring Low Density Lipoprotein Uptake in Homozygous Familial Hypercholesterolemia.

Author information

1
Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, Takara-machi 13-1, Kanazawa, Ishikawa, 920-8641, Japan.
2
Department of Immunology, Kanazawa University Graduate School of Medicine, Takara-machi 13-1, Kanazawa, Ishikawa, 920-8640, Japan.
3
Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, Takara-machi 13-1, Kanazawa, Ishikawa, 920-8641, Japan. m-yamagishi@kun.ohs.ac.jp.
4
Department of Human Sciences, Osaka University of Human Sciences, 1-12-13 Shoya, Settsu, Osaka, 566-8501, Japan. m-yamagishi@kun.ohs.ac.jp.

Abstract

Gene correction of induced pluripotent stem cells (iPSCs) has therapeutic potential for treating homozygous familial hypercholesterolemia (HoFH) associated with low-density lipoprotein (LDL) receptor (LDLR) dysfunction. However, few data exist regarding the functional recovery and immunogenicity of LDLR gene-corrected iPSC-derived hepatocyte-like cells (HLCs) obtained from an HoFH patient. Therefore, we generated iPSC-derived HLCs from an HoFH patient harbouring a point mutation (NM_000527.4:c.901 G > T) in exon 6 of LDLR, and examined their function and immunogenicity. From the patient's iPSCs, one homozygous gene-corrected HoFH-iPSC clone and two heterozygous clones were generated using the CRISPR/Cas9 method. Both types of iPSC-derived HLCs showed recovery of the function of LDL uptake in immunofluorescence staining analysis. Furthermore, these gene-corrected iPSC-derived HLCs showed little immunogenicity against the patient's peripheral blood mononuclear cells in a cell-mediated cytotoxicity assay. These results demonstrate that LDL uptake of iPSC-derived HLCs from HoFH can be restored by gene correction without the appearance of further immunogenicity, suggesting that gene-corrected iPSC-derived HLCs are applicable to the treatment of HoFH.

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