Progress Update: Screening of FDA-approved compounds

See grant Screening of FDA-approved compounds with DUX4-inhibitory potential in a FSHD mouse model

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy, affecting roughly 1: 8,000 individuals. While consensus has emerged on a toxic protein called DUX4 as the causative factor for this disease, there is currently no treatment or cure. Our lab has previously identified novel targets that contribute to how DUX4 causes toxicity and demonstrated that using drugs to block these targets can reduce DUX4 toxicity in cell culture. The goal of our project is to use a previously published mouse model of FSHD to establish a pipeline for testing the therapeutic potential of the drugs we identify, starting with everolimus.

This mouse model allows for DUX4 expression specifically in the skeletal muscle making it a good mimic of the disease and the amount of DUX4 expression can be adjusted to change the severity of muscle weakness. During the first half of this project we have been establishing an optimal amount of muscle weakness to be able to maximize our chance of detecting improvements with everolimus. We have also been establishing the tests to use that will determine a benefit. These tests can be divided into several parts. First, is the detection of DUX4 expression in the muscle as well as detection of DUX4 targets in order to determine if DUX4 activity can be blocked. Second, is detecting tissue damage from DUX4 expression. This includes signs of cell death, inflammation and fat deposition, all features of FSHD. Third are physical assays to determine if everolimus can improve muscle function. This included treadmill endurance and grip strength measurements and will soon include muscle contraction measurements. We have begun to test everolimus with this model but do not have enough data to make any determination at this point.

Moving forward we will continue to optimize our procedures and everolimus dosing in this mouse model. A therapeutic effect with everolimus if detected would be a major benefit for the FSHD field as it is already FDA-approved for other conditions, reducing the time it would need to spend in clinical trials. This work will also provide a system for us to screen other drugs in our lab that show therapeutic potential in cells. By increasing the number of compounds studied, we increase our chance of FSHD patients ultimately having a treatment or cure.