ArticleProceedings of the National Academy of Sciences of the United States of America2019
Humanized UGT2 and CYP3A transchromosomic rats for improved prediction of human drug metabolism.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 40 citations in OpenAlex.
- Double-humanized Rats for CYP3A and PXR as an Improved Model for Analyzing Drug-drug Interactions Mediated by CYP3A4.The AAPS journal · 2025Article
- Titin fragment is a sensitive biomarker in Duchenne muscular dystrophy model mice carrying full-length human dystrophin gene on human artificial chromosome.Scientific reports · 2025Article
- Pharmacokinetic Interaction Between Olaparib and Regorafenib in an Animal Model.Pharmaceutics · 2024Article
- Induction of hepatic CYP3A4 expression by cholesterol and cholic acid: Alterations of gene expression, microsomal activity, and pharmacokinetics.Pharmacology research & perspectives · 2024Article
- Construction and characterization of a humanizedActa pharmaceutica Sinica. B · 2024Article
- Rapid human genomic DNA cloning into mouse artificial chromosome via direct chromosome transfer from human iPSC and CRISPR/Cas9-mediated translocation.Nucleic acids research · 2024Article
- Phenotypic features of dystrophin gene knockout pigs harboring a human artificial chromosome containing the entire dystrophin gene.Molecular therapy. Nucleic acids · 2023Article
- Simultaneous loading of PCR-based multiple fragments on mouse artificial chromosome vectors in DT40 cell for gene delivery.Scientific reports · 2022Article
- Analysis of in vitro and in vivo metabolism of zidovudine and gemfibrozil in trans-chromosomic mouse line expressing human UGT2 enzymes.Pharmacology research & perspectives · 2022Article
- Panel of human cell lines with human/mouse artificial chromosomes.Scientific reports · 2022Article
- A transchromosomic rat model with human chromosome 21 shows robust Down syndrome features.American journal of human genetics · 2022Article
- Construction of stable mouse artificial chromosome from native mouse chromosome 10 for generation of transchromosomic mice.Scientific reports · 2021Article
- Highly Efficient Microcell-Mediated Transfer of HACs Containing a Genomic Region of Interest into Mammalian Cells.Current protocols · 2021Article
- Blastocyst complementation using Prdm14-deficient rats enables efficient germline transmission and generation of functional mouse spermatids in rats.Nature communications · 2021Article
- Rat models of human diseases and related phenotypes: a systematic inventory of the causative genes.Journal of biomedical science · 2020Review
- A non-mosaic transchromosomic mouse model of down syndrome carrying the long arm of human chromosome 21.eLife · 2020Article
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Authors and funding
25 authors at 11 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Although "genomically" humanized animals are invaluable tools for generating human disease models as well as for biomedical research, their development has been mainly restricted to mice via established transgenic-based and embryonic stem cell-based technologies. Since rats are widely used for studying human disease and for drug efficacy and toxicity testing, humanized rat models would be preferred over mice for several applications. However, the development of sophisticated humanized rat models has been hampered by the difficulty of complex genetic manipulations in rats. Additionally, several genes and gene clusters, which are megabase range in size, were difficult to introduce into rats with conventional technologies. As a proof of concept, we herein report the generation of genomically humanized rats expressing key human drug-metabolizing enzymes in the absence of their orthologous rat counterparts via the combination of chromosome transfer using mouse artificial chromosome (MAC) and genome editing technologies. About 1.5 Mb and 700 kb of the entire UDP glucuronosyltransferase family 2 and cytochrome P450 family 3 subfamily A genomic regions, respectively, were successfully introduced via the MACs into rats. The transchromosomic rats were combined with rats carrying deletions of the endogenous orthologous genes, achieved by genome editing. In the "transchromosomic humanized" rat strains, the gene expression, pharmacokinetics, and metabolism observed in humans were well reproduced. Thus, the combination of chromosome transfer and genome editing technologies can be used to generate fully humanized rats for improved prediction of the pharmacokinetics and drug-drug interactions in humans, and for basic research, drug discovery, and development.
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