Keynote presentation 8: JPS Lecturer
| Wednesday, December 4, 2024 |
| 1:10 PM - 2:00 PM |
| Goldfields Theatre |
Details
Deep-intronic mutations often distort splicing regulatory motifs and some intronic sequences are retained as exons, which are referred to as pseudo exon. In 2002, A single G→A intronic mutation (IVS4+919G→A) of α-galactosidase A (-Gal A) gene was identified in a patient with cardiac Fabry disease who has the concentric left ventricular hypertrophy. The mutation promotes recognition of intronic 57-nucleotide sequence as a pseud exon in the a-Gal A transcript, which is not translated and subsequently leads to accumulation of of globotriaosylceramide (Gb3) in lysosomes of heart. Unexpected high prevalence of the cardiac variant Fabry mutation IVS4+919G→A was reported among both newborns (≈1 in 1600 males) and patients with idiopathic hypertrophic cardiomyopathy in Taiwan. As enzyme replacement therapy is not so effective for the cardiac phenotype, we have started to screen synthetic chemicals with our splicing reporter system to look for a druggable small compound which can normalize the aberrant splicing of -Gal A transcript. Newly found compound induced CLK1 activity, promoted phosphorylation of SRSF6, recovered normal splicing of -Gal A mRNA, increased the enzyme activity, and reduced Gb3 amount in the patient iPS cells. The splicing therapy with chemical splicing modulators can be applicable for other inherited diseases such as familial dysautonomia and several types of long QT syndrome caused by aberrant splicing.
Speaker
Prof Masatoshi Hagiwara
Kyoto University
Therapeutic molecules to rectify aberrant RNA splicing
Biography
He graduated Mie University School of Medicine in 1984 and took Ph.D in Department of Pharmacology by finding the inhibitory mechanism of isoquinolinesulfonamide compounds on protein kinases in 1988. One of them, fasudil, was developed as a clinical drug to prevent vasoconstriction after subarachnoid haemorrhage. In the Salk Institute, he found that transcriptional attenuation following PP-1-mediated dephosphorylation of CREB and succeeded to identify CBP as the phosphorylated CREB binding protein. When he returned to Japan in 1993, he started his own laboratory in Nagoya University School of Medicine as Assistant Professor. He moved to Tokyo in 1997 as Professor of Medical Research Institute of Tokyo Medical and Dental University, and decided to try to decipher splicing code to cure genetic diseases. He moved from Tokyo to Kyoto University in 2010 as Professor and Chairman of Department of Anatomy and Developmental Biology, Graduate School of Medicine.
Chair
Alastair Stewart
Director Of ARC Centre For Personalised Therapeutics Technologies
The University of Melbourne
