Integrative Analysis of Drug-Gene Expression Signatures in Human Pluripotent Stem Cells Identifies Novel Drug Candidates for ALS and Monogenic Diseases

The classical paradigm of drug screening often faces significant limitations due to the challenges associated with identifying molecular or cellular read-outs that are relevant to specific diseases. This issue is particularly pronounced for the thousands of diseases of genetic origin, given the abundance of databases listing disease-associated changes in gene expression and various transcripts, indicating that potential read-outs may be concealed within these resources. To remedy this, an alternative approach was tested: compounds were evaluated for their effects on gene expression and alternative splicing in a healthy cell model, and the resulting data were matched to molecular signatures of diseases. A subset of 50 FDA-approved drugs was tested on mesenchymal stem cells derived from a human pluripotent stem cell line. Over half of the compounds altered gene expression, many affecting pathways linked to monogenic diseases. One hit, increased SQSTM1 expression induced by prazosin, was further validated in ALS models caused by SQSTM1 haploinsufficiency, including patient-derived fibroblasts, SQSTM1-depleted hiPSC-derived motor neurons, and a zebrafish model. Extending this paradigm could involve testing diverse cell types and larger drug libraries. One Sentence SummaryA novel drug screening approach for monogenic diseases integrating human pluripotent stem cell derivatives and RNA sequencing to profile gene expression.