Progress Update: Development of novel DUX4-targeted miR-675-based therapies for FSHD

Update by Dr. Saad
See grant Development of novel DUX4-targeted miR-675- based therapies for FSHD

Facioscapulohumeral dystrophy (FSHD) is a genetic muscle disease caused by the unusual presence of DUX4 in skeletal muscles. As a result, skeletal muscles become damaged and weak. In our proposed project, we developed two therapeutic strategies for FSHD. These strategies rely on the power of natural small molecules called “microRNAs” that are normally found in many human tissues, among them skeletal muscles. The natural function of these microRNAs is to decrease the levels of proteins in a cell. Each microRNA can specifically decrease the level of one or more proteins. In fact, a microRNA becomes more efficient in decreasing the levels of its target protein when it becomes more abundant in the cell. Accordingly, in our 1st therapeutic strategy, we used adeno-associated virus (AAV)-based gene therapy to deliver our microRNA into mice skeletal muscles expressing DUX4. Our results are very promising as our natural microRNA was able to efficiently prevent the production of DUX4 and thus prevented DUX4 from damaging muscle. In our second therapeutic strategy, we used pharmaceutical drugs to increase the abundance of our natural microRNA in human skeletal muscle cells. This strategy showed very promising results as these drugs were able to efficiently reduce DUX4 and DUX4-associated biomarkers. This work was recently accepted for publication in Nature Communications, a high impart journal publishing original research articles. In an effort to investigate toxicity of our miRNA constructs, we looked for changes in expression of off-target genes using cultured human skeletal muscle cells. As a result, our data did not show any alarming changes in gene expression. Following this, we then tested the inhibition efficiency of our natural microRNA in our FSHD mouse model (TIC-DUX4 mouse), and its effect on skeletal muscle beyond DUX4 targeting. Our results show that in addition to being efficient in reducing DUX4-induced damage in skeletal muscles, this microRNA was able to target an essential component regulating skeletal muscle size. Finally, our drug-based therapy aiming to increase the level of this natural microRNA in skeletal muscles was also promising as we were able to identify 3 drug candidates capable of increasing the microRNA levels and decreasing DUX4 and DUX4-responsive biomarkers in 3 different skeletal muscle cell lines. This project is very promising as it would lay the ground to bring to the clinic a therapeutic natural microRNA and pharmaceutical drugs that increase its level. As a result, these therapies will eliminate DUX4 from skeletal muscles, stop muscle degradation and possibly enhance muscle regeneration, allowing not just the recovery of skeletal muscles but also allowing them to become stronger.