Integrative analysis of drug-gene signatures in human pluripotent stem cells reveals prazosin as a novel SQSTM1 regulator for ALS therapeutics

Reverse phenotypic mapping identifying prazosin as an inducer of *SQSTM1* expression

A reverse phenotypic mapping approach tested the effect of 50 drugs on gene expression and alternative splicing in mesenchymal stem cells derived from human iPSCs, then matched the resulting signatures to monogenic disease signatures. One hit, prazosin-induced increase of SQSTM1 expression, was validated in FTD/ALS type 3 models caused by SQSTM1 haploinsufficiency: patient fibroblasts, SQSTM1-depleted iPSC-derived motor neurons, and a zebrafish model. The work proposes a drug-repurposing paradigm based on transcriptomic signatures.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The interest of this paper lies in the strategy: exploiting drug-gene signatures to reposition an existing molecule (prazosin) toward a haploinsufficiency — here SQSTM1 — rather than targeting a hard-to-establish specific read-out. Multi-model validation is encouraging, but the work remains preclinical with no in vivo patient data. An appealing treatment lead for haploinsufficiency forms, pending confirmation.