The utilization of gene targeting models during in preclinical study of drug discovery process--example of phenotypic and functional analysis of Cacna1beta gene product.
Using gene knockout mice of particular genes is one of the most effective methods in conducting successful study on the mode of action of target gene products in targeted organs. So called the knockout technology is now a powerful tool that can lead us to find clear understanding on difficult questions such as the effects of full antagonist against target molecules. Cacna1b (alpha(1B)) gene knockout mouse was generated to study mechanisms of N-type calcium (Ca(2+)) channel. The model was able to overcome physiological obstacles in studies of N-type Ca(2+) channel selective blockers, such as unspecific binding to structurally similar molecules, and failed distribution to targeted organs. In the case of N-type Ca(2+) channel studies, knockout technology was successfully applied to various cardiovascular, sympathetic, nociceptive, sleep-awake cycles, metabolic and neurodegenerative experiments using homozygous mutants of the alpha(1B) gene that turned out to be viable. These studies were able to confirm not only the predicted phenotypes, but were able to present completely unexpected phenotypes that are great interest for future study. Thus the outputs from the knockout mouse studies lead to gain the proof of concept as a drug for specific inhibitors of the gene products and enabled us to make further prediction of side-effects of these inhibitors in the drug discovery and development process.
Miyamoto
Norimasa
N
Laboratory of Core Technology, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. n-miyamoto@hhc.eisai.co.jp
Namiki
Kana
K
Tokuhara
Naoki
N
Uesugi
Mai
M
Takahashi
Eiki
E
Kuromitsu
Junro
J
Kasuya
Yoshitoshi
Y
D000818:Animals; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000494:pharmacology*; D020864:Calcium Channels, N-Type / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018390:Gene Targeting; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011237:Predictive Value of Tests
C500963:Cacna1b protein, mouse; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type