Progress Update: DUX4 mRNA silencing using RNA editing

Update by Dr. Scott Harper
See grant DUX4 mRNA silencing using RNA editing by CRISPR-Cas13-ADAR2 and endogenous ADAR

After many years of research, we now know that FSHD is caused by the toxic DUX4 gene being turned on in muscle cells. Discovery of the DUX4 disease gene provided an important target for developing FSHD therapies. These therapies aim to stop the DUX4 gene from being made and help reduce the damage it causes in muscle. In this proposal, we aim to develop a new approach for treating FSHD by using a cutting-edge technique called RNA editing. When a gene is turned on, it produces a “messenger RNA,” which is then translated into a protein that performs functions in the cell. The messenger RNA is a critical intermediate for making a gene into a protein. RNA editing technology allows us to disrupt that messenger RNA – and specifically the DUX4 messenger RNA – so that it cannot direct production of toxic DUX4 protein. In this proposal, we hypothesize that DUX4 RNA editing can be a powerful tool for making changes in the DUX4 RNA, and by doing so we can make it less toxic to muscle cells. So far, we have been able to induce RNA editing activity at one site in the DUX4 messenger RNA. However, the efficiency is so far relatively low.  Our ongoing experiments aim to target additional sites in the messenger RNA to see if some editing sites work better than others. We will also work to improve the efficiency of the RNA editing to have the biggest reduction in DUX4 protein as possible. We will next explore if the RNA editing we have done to the DUX4 messenger RNA reduces the toxicity of DUX4 protein in cells. We hope that this research will build a foundation for a potential FSHD therapeutic approach.