In higher eukaryotes, RNAs are subjected to several post-transcriptional regulations. Disruption of these regulations often results in the causes of diseases, called as “RNA diseases”. We have been analyzing the mechanism of RNA diseases, including Familial Dysautonomia (FD).

                FD is a devastating hereditary sensory and autonomic neuropathy, caused by a mutation in the IκB kinase associated protein gene (IKBKAP). This mutation is in the 5^’ splice site of intron 20 in the IKBKAP gene that leads to exon20 skipping and reduction of IKAP protein especially in neurons. To analyze the molecular mechanism of abnormal splicing in FD patients, we have set up multi-color reporter system by using a portion of human IKBKAP gene expanding from exon19 to exon21. Our dual-color reporter system, named SPREADD (SPlicing REporter Assay system for Disease genes with Dual color), successfully recapitulates abnormal splicing of FD patients in culture cells. By using this system, we screened small molecules that enhance exon 20 inclusion and increase the amount of normal IKAP protein. We succeeded in identifying a small molecule that enhanced the inclusion of exon 20 and increased IKAP expression in cells from the FD patients. We named this small molecule RECTAS (RECTifier of Aberrant Splicing). Furthermore, RECTAS recovered the defect in proliferation of cells derived from the FD patient. These results suggest that RECTAS is a promising candidate of the therapeutic drug for FD. Our findings may open the way to develop a new type of tailor-made medicine of RNA diseases.