Synthetic compounds to normalize aberrant splicing of genetic diseases

[Speaker] Masatoshi Hagiwara:1
1:Department of Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Japan

Patients of congenital diseases have abnormalities in their chromosomes and/or genes. Therefore, it has been considered that drug treatments can serve to do little for these patients more than to patch over each symptom temporarily when it arises. Although we cannot normalize their chromosomes and genes with chemical drugs, we may be able to manipulate the amounts and patterns of mRNAs transcribed from patients DNAs with small chemicals. Based on this simple idea, we have looked for chemical compounds which can be applicable for congenital diseases and found INDY, TG003, and SRPIN340 are promising as clinical drugs for Down syndrome (ref 1) and Duchenne muscular dystrophy (ref 2), respectively.
Familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy, is caused by mis-splicing resulting from an intronic mutation in IKBKAP gene. FD would be treatable if we can develop "a splicing modulator" which promotes exon20 inclusion of IKBKAP and increases the expression of IKAP protein in FD patient cells. In order to find the modulator, we established splicing reporter assay with dual color (SPREAD) using a segment of human IKBKAP spanning from exon19 to exon21. SPREAD allows us to visualize the splicing in cells, and to identify RBM24 and RBM38 as the tissue-specific modulators for exon20 inclusion of IKBKAP. This also enabled us to find a chemical compound RECTAS, which can rectify the aberrant IKBKAP splicing in FD patient fibroblasts. Our data implicate the mis-splicing of IKBKAP in the reduced tRNA modification in FD patient and demonstrated that RECTAS could be the therapeutic drug (ref 3). Recently, we found small molecules which can normalize aberrant splicing and are potentially applicable for cardiac Fabry disease and Cystic fibrosis (unpublished).

1. Nakano-Kobayashi A et al. (2017) Prenatal neurogenesis induction therapy normalizes brain structure and function in Down syndrome mice. Proc Natl Acad Sci USA.114(38):10268-10273.
2. Nishida A et al. (2011) Chemical treatment enhances skipping of a mutated exon in the dystrophin gene. Nature Communications 2, 308. doi: 10.1038/ncomms1306.
3. Yoshida M et al. (2015) Rectifier of aberrant mRNA splicing recovers tRNA modification in familial dysautonomia. Proc Natl Acad Sci USA. 112(9):2764-2769.

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