Treatment with hepatocyte transplantation in a novel mouse model of persistent liver failure

Tamaki, Yuki; Shibata, Yuria; Hayakawa, Misaki; Kato, Nodoka; Machii, Ami; Ikeda, Yoshikazu; Nanizawa, Eri; Hayashi, Yoshinori; Suemizu, Hiroshi; Ito, Hiroyasu; Ishikawa, Tetsuya

doi:10.1016/j.bbrep.2022.101382

Cited by 1 publication

(1 citation statement)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nonetheless, these methods require hepatocyte injury to host hepatocytes induced by toxic transgenes 25 and relied on recipient mice being highly immunocompromised to decrease hepatocyte rejection and enable engraftment, such as the Fah -/- , Rag2 -/- , IL2rg -/- (FRG) mouse. Recently, Tamaki et al could show up to 70% stable liver repopulation upon autologous primary hepatocyte transplantation using fully immune competent mice, where allogenic primary hepatocyte transplantation was unsuccessful 26 . Unlike FAH deficient and uPA over-expressing hepatocytes, Cypor -inactivated hepatocytes have a selective advantage over “normal” hepatocytes making it a highly promising and versatile method to select for genetically modified hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic liver cell transplantation to treat a genetic liver defect

Willimann,

Grisch-Chan,

Rimann

et al. 2024

Preprint

View full text Add to dashboard Cite

For gene therapy of the liver,in vivoapplications based on adeno-associated virus are the most advanced vectors despite limitations, including low efficacy and episomal loss, potential integration and safety issues, and high production costs. Alternative vectors and/or delivery routes are of high interest. The regenerative ability of the liver bears the potential forex vivotherapy using liver cell transplantation for disease correction if provided with a selective advantage to expand and replace the existing cell mass. Here we present such treatment of a mouse model of human of phenylketonuria (PKU). Primary hepatocytes from wild-type mice were gene modifiedin vitro(with a lentiviral vector) that carries a gene editing system (CRISPR) to inhibitCypor.Cyporinactivation confers paracetamol (or acetaminophen) resistance to hepatocytes and thus a growth advantage to eliminate the pre-existing liver cells upon grafting (via the spleen) and exposure to repeated treatment with paracetamol. GraftingCypor-inactivated wild-type hepatocytes into inbred young adultenu2(PKU) mice, followed by selective expansion by paracetamol dosing resulted in replacing up to 5% of cell mass, normalization of blood phenylalanine and permanent correction of PKU. Hepatocyte transplantation offers thus an armamentarium of novel therapy options for genetic liver defects.

show abstract

Section: Introductionmentioning

confidence: 99%