Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance mechanism that eliminates aberrant mRNAs carrying premature termination codons (PTCs). Up to 30% of all known mutations causing human diseases generate aberrant mRNAs that are degraded by NMD. NMD degrades not only proteins that show dominant-negative function but also aberrant proteins that retain at least some aspect of their normal cell function. If mutant proteins are still functional, the selective inhibition of NMD provides a strategy to ameliorate disease phenotypes in patients with PTC-related conditions. Another strategy to inhibit NMD for the rescue of intractable diseases involves drugs causing translational readthrough as NMD inhibition expected in a synergistic effect on read-through efficiency. Importantly, suppression of NMD causes an enhancement of tumor immunity; suppression of NMD causes induction of tumor specific neoantigen that induce tumor immunity in mice model. The bottleneck of these strategy for the treatment of intractable diseases is a “pure” NMD inhibitor. Although recent studies have reported the identification of novel NMD inhibitors, for most of them, NMD inhibitor could not be confirmed by other laboratories. Hence, the identification of a potent “pure” NMD inhibitor is desired. 

In this project, we will demonstrate NMD suppression at mouse level using our novel NMD inhibitor (P-DIRECT, patent pending) and several existing drugs that induce NMD inhibition (unpublished), which were discovered using our NMD evaluation system (patent pending). By using these NMD inhibitors, we will establish a method for the treatment of cancer immunity and genetic diseases containing nonsense-mRNA. In parallel, in order to obtain more effective compounds, we will conduct screening using the Okinawa natural compound library of the University of the Ryukyus and the compound library of the Drug Discovery Initiative using our NMD or read-through evaluation systems. As a cancer model, we will use a transplantation model using mouse melanoma cells. As a model for the treatment of genetic diseases, we will use cystic fibrosis nonsense mutant mice that we established. Through these analyses, we will obtain proof of concept at the in vivo level. We will also consider the analysis of NMD inhibition in patients treated with existing drugs with NMD inhibitory activity at the University Hospital of the Ryukyus. 

The goal of the study is to strengthen the rational of the strategy by obtaining the proof of concept for the induction of nonsense-mRNA via inhibition of NMD against intractable cancers and rear genetic disease.