Evaluation of the potential risk of drug induced mood disturbance and suicide: use of a dedicated platform

摘要

The present invention relates to in vitro methods for the determination of the potential toxicity of test compounds. The invention also comprises in vitro methods for the selection of therapeutical compounds useful for the treatment of pathology related to an alteration of the mechanism of the mRNA editing of ADAR dependent A to I mRNA editing of the serotonin 2C receptor (5HTR2C). Finally, the present invention is directed to the kits and tools for the implementation of these methods. The invention is of special utility in the pharmaceutical industry for analysis of the toxicity profile or the screening of compounds involved in drug development and/or in pharmaceutical compositions.

主权项

1. An in vitro method comprising the following steps of:
a) obtaining a biological sample containing mammal cells wherein said mammal cells are cell lines of human origin which exhibit a regular and constitutive expression of the editing enzymes ADAR1a, ADAR1b and ADAR2 and of the serotonin 2C receptor (5HTR2C); b) contacting said mammals cells with the compound to be tested; c) determining in the cellular RNA extract of said biological sample: the editing profile giving the mean proportion of each identified isoform of the 5-HT2CR mRNA measured in the cellular RNA extract, and the quantitative expression of said editing enzymes ADAR1a, ADAR1b and ADAR2; d) comparing the results obtained in step c) between said treated cells with the compound to be tested and non treated control cells, and e) determining the potential toxicity or side-effects of a test compound after its administration in a patient, wherein in step a), said mammal cells are from the human neuroblastoma SH-SY5Y cell line.