Transcriptome signature analysis repurposes trifluoperazine for the treatment of fragile X syndrome in mouse model

Abstract

Fragile X syndrome (FXS) is a prevailing genetic disorder of intellectual disability and autism. There is no efficacious medication for FXS. Through in silico screening with a public database, computational analysis of transcriptome profile in FXS mouse neurons predicts therapeutic value of an FDA-approved drug trifluoperazine. Systemic administration of low-dose trifluoperazine at 0.05 mg/kg attenuates multiple FXS-and autism-related behavioral symptoms. Moreover, computational analysis of transcriptome alteration caused by trifluoperazine suggests a new mechanism of action against PI3K (Phosphatidylinositol-4,5-bisphosphate 3kinase) activity. Consistently, trifluoperazine suppresses PI3K activity and its down-stream targets Akt (protein kinase B) and S6K1 (S6 kinase 1) in neurons. Further, trifluoperazine normalizes the aberrantly elevated activity of Akt and S6K1 and enhanced protein synthesis in FXS mouse. Together, our data demonstrate a promising value of transcriptome-based computation in identification of therapeutic strategy and repurposing drugs for neurological disorders, and suggest trifluoperazine as a potential treatment for FXS.

Vorinostat corrects cognitive and non-cognitive symptoms in a mouse model of fragile X syndrome

“…Among the predicted drugs, an FDAapproved antipsychotics trifluoperazine causes transcriptome alteration oppositional to that caused by FMRP deficiency. It was further demonstrated that trifluoperazine corrects the key FXS-associated symptoms in the Fmr1 KO mice 12 . Moreover, computational analysis of the trifluoperazine-induced transcriptome signature revealed other similarity drugs, predicting that those similarity drugs may be repurposed to treat FXS.…”

“…The search for drugs/compounds that induce similar transcriptome changes to that of vorinostat in the CMap database was performed as described 12 . In brief, we first obtained microarray data sets of MCF7, PC3, and HL60 cells treated with vorinostat and the corresponding vehicle controls.…”

“…In brief, we first obtained microarray data sets of MCF7, PC3, and HL60 cells treated with vorinostat and the corresponding vehicle controls. The differential gene expression analysis was conducted, and the top 500 up-regulated and down-regulated genes were retained as the signature for further query 12,17,18 . The transcriptome signature of vorinostat was uploaded to the CMap query page and used to search for compounds that induce similar or oppositional transcriptome changes in the corresponding cell line (i.e., MCF7, PC3, and HL60) 9 .…”

“…Mouse activity in the light/dark box, the open field, and the 3-chamber social interaction test was examined as described in our previous studies 3,12,19 .…”

“…More recently, computational comparison of drug-induced transcriptome profiles has been proposed as a non-structure based in-silico screening of similarity drugs [9][10][11] . By using such a computation approach, our recent study predicts that the FDA-approved drug vorinostat may have therapeutic effects to correct FXS-associated symptoms 12 . However, the prediction requires empirical validation.…”