Transcriptomic RNAseq drug screen in cerebrocortical cultures: toward novel neurogenetic disease therapies

Hum Mol Genet. 2018 Sep 15;27(18):3206-3217. doi: 10.1093/hmg/ddy221.

Abstract

Rare monogenic diseases affect millions worldwide; although over 4500 rare disease genotypes are known, disease-modifying drugs are available for only 5% of them. The sheer number of these conditions combined with their rarity precludes traditional costly drug discovery programs. An economically viable alternative is to repurpose established drugs for rare diseases. Many genetic diseases result from increased or decreased protein activity and identification of clinically approved drugs which moderate this pathogenic dosage holds therapeutic potential. To identify such agents for neurogenetic diseases, we have generated genome-wide transcriptome profiles of mouse primary cerebrocortical cultures grown in the presence of 218 blood-brain barrier (BBB) penetrant clinic-tested drugs. RNAseq and differential expression analyses were used to generate transcriptomic profiles; therapeutically relevant drug-gene interactions related to rare neurogenetic diseases identified in this fashion were further analyzed by quantitative reverse transcriptase-polymerase chain reaction, western blot and immunofluorescence. We have created a transcriptome-wide searchable database for easy access to the gene expression data resulting from the cerebrocortical drug screen (Neuron Screen) and have mined this data to identify a novel link between thyroid hormone and expression of the peripheral neuropathy associated gene Pmp22. Our results demonstrate the utility of cerebrocortical cultures for transcriptomic drug screening, and the database we have created will foster further discovery of novel links between over 200 clinic-tested BBB penetrant drugs and genes related to diverse neurologic conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / drug effects
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects*
  • Drug Evaluation, Preclinical*
  • Gene Expression Regulation / drug effects
  • Genome, Human / drug effects
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Mice
  • Peripheral Nervous System Diseases / drug therapy*
  • Peripheral Nervous System Diseases / pathology
  • Transcriptome / genetics*

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