Establishment of SLC15A1/PEPT1-Knockout Human-Induced Pluripotent Stem Cell Line for Intestinal Drug Absorption Studies

Molecular Therapy: Methods & Clinical Development

Hiroyuki Mizuguchi¹  Kazumasa Hirata²  Kazuo Harada²  Tomoki Yamashita³  Sayaka Deguchi³  Ryosuke Negoro³  Moe Ichikawa⁴  Kanae Kawai⁴  Kazuo Takayama⁴ 

[1] Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan;Laboratory of Applied Environmental Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan;Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan;Laboratory of Biochemistry and Molecular Biology, School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan;

关键词: human iPS cells;    intestinal epithelial-like cells;    SLC15A1;    PEPT1;    genome editing;    CRISPR-Cas9;   

DOI  :  

来源: DOAJ

【 摘 要 】

Because many peptide and peptide-mimetic drugs are substrates of peptide transporter 1, it is important to evaluate the peptide transporter 1-mediated intestinal absorption of drug candidates in the early phase of drug development. Although intestinal cell lines treated with inhibitors of peptide transporter 1 are widely used to examine whether drug candidates are substrates for peptide transporter 1, these inhibitors are not sufficiently specific for peptide transporter 1. In this study, to generate a more precise evaluation model, we established peptide transporter 1-knockout induced pluripotent stem cells (iPSCs) by using a CRISPR-Cas9 system and differentiated the cells into intestinal epithelial-like cells. The permeability value and uptake capacity of glycylsarcosine (substrate of peptide transporter 1) in peptide transporter 1-knockout intestinal epithelial-like cells were significantly lower than those in wild-type intestinal epithelial-like cells, suggesting that peptide transporter 1 was successfully depleted in the epithelial cells. Taken together, our model can be useful in the development of peptide and peptide-mimetic drugs.

【 授权许可】

Unknown