Investigators: Angela Lek PhD, Monkol Lek PhD
Category: Research - Translational
There is currently no treatment for Facioscapulohumeral muscular dystrophy (FSHD), one of the most prevalent forms of muscular dystrophy. Unlike classical forms of muscular dystrophies, FSHD has unique underlying genetics, which hinders the effectiveness of gene replacement therapies that have shown promise for other disorders. Alternative approaches are therefore desired and the fastest way to translate a therapy into the clinic and patients is to use FDA--approved drugs that are already proven to be safe for use in humans. The million-- dollar question is whether there are any out there that can neutralize the toxic effect of DUX4 -- the disease--causing gene behind FSHD.
We set out to answer this question using a powerful cell--screening approach in an attempt to identify genes whose loss--of--function resulted in disabling of DUX4’s toxic effect; in other words, causing resistance to DUX4. Based on the identified genes, we were able to map out key cellular pathways involved in causing DUX4’s toxic effect, which gave us clues to the types of drugs that can cause resistance to DUX4. Following this, we sought FDA--approved compounds that target these same cellular pathways and tested them in patient cells and a zebrafish model of FSHD. Our results demonstrated that these compounds were able to reduce the molecular signatures of FSHD in patient cells and were also able to correct the muscle--associated phenotypes in our zebrafish model.
We now intend to perform pre--clinical studies in mice with one of the most promising compounds identified targeting mTOR signaling. In these studies, we will assess whether the drug can correct muscle weakness in a DUX4 mouse model and show improvements in muscle function such as contractile force, grip strength and running times. We will also investigate whether the drug can successfully reduce levels of DUX4 expression on a molecular level and reduce the amount of cell death and inflammation/fibrosis in mouse muscle.
It is our hope that successful completion of these experiments and positive results with this drug will lead to human clinical trials and a faster time towards availability of a treatment for FSHD patients.
Note: Due to pandemic lockdowns, a no-cost 4 month extension was granted.