Target identification using genetically engineered models
Genetic ablation or transgenic studies on the Tg-SOD1G93A background may unravel new targets for ALS treatment but may not always be of direct clinical relevance since genetic modification has already taken place at the embryo stage and well-before disease symptoms appear. Drugs are administered when diagnosis has been made, that for ALS may take up to 12 months after the appearance of symptoms. In this sense, a marginal effect on symptoms or life extension after deletion of a gene in an ALS mouse model could indicate that pharmacological targeting of the gene-encoded protein will not be effective in patients. Inducible knockout models or inducible transgenic models on an ALS background (e.g.Tg-SOD1G93A ) will provide a more sophisticated practice to search for relevant pharmacological targets since it will allow genetic modification to take place after the appearance of symptoms. In this direction, it has been demonstrated that reduction ofEPHA4 in adulthood does not affect survival of Tg-SOD1G93A mice (Rué et al., 2019). Thus, chemical targeting of EPHA4 after the onset of symptoms may not delay disease progression. Finally, extrapolation of animal data to humans should be made in a very cautious manner since mouse models may not recapitulate human ALS, thus some compounds that were found effective in treating mice may not be beneficial to patients. Nevertheless, this problem may be more pronounced when extrapolating data from more distant drosophila and zebrafish.