Use of Ultrasound to Assess Drug Efficacy in Orthotopic Rat Models of HCC

Abstract B170: Novel immunodeficient rat models offer a unique platform for drug efficacy studies in human tumor xenografts

10.1158/1535-7163.targ-17-b170 ◽

2018 ◽

Author(s):

Kamesh Ravi ◽

Fallon Noto ◽

Christopher McClain ◽

Angela Arey ◽

Goutham Narla ◽

...

Keyword(s):

Human Tumor ◽

Drug Efficacy ◽

Human Tumor Xenografts ◽

Rat Models ◽

Tumor Xenografts ◽

Efficacy Studies

Download Full-text

Humanized UGT2 and CYP3A transchromosomic rats for improved prediction of human drug metabolism

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1808255116 ◽

2019 ◽

Vol 116 (8) ◽

pp. 3072-3081 ◽

Cited By ~ 9

Author(s):

Yasuhiro Kazuki ◽

Kaoru Kobayashi ◽

Masumi Hirabayashi ◽

Satoshi Abe ◽

Naoyo Kajitani ◽

...

Keyword(s):

Genome Editing ◽

Human Disease ◽

Embryonic Stem ◽

Toxicity Testing ◽

Drug Efficacy ◽

Basic Research ◽

Gene Clusters ◽

Artificial Chromosome ◽

Rat Models ◽

Chromosome Transfer

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.

Download Full-text