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 aimed 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 proposed to test several RNA editing strategies to that we predicted would produce a less toxic or non-toxic DUX4 protein.  This is a large project requiring us to produce new cell lines and generate hundreds of DNAs that are capable of directing RNA editing.  As of this writing, this project is still ongoing, and so far, we have been able to induce RNA editing activity at one site in the DUX4 messenger RNA.

Importantly, we used the data and strategies developed in this Friends of FSH Research project to support a large, 5-year grant application to the NIH, and it was recently awarded in August 2021.  We are grateful to the Friends of FSH Research and their donors for supporting our work and catalyzing a new project.

CRISPR-Cas13 gene therapy and RNA editing for Facioscapulohumeral muscular dystrophy