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.