Progress Update: Screening of FDA-approved compounds

Update provided by Dr. Angela Lek
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 our first candidate, everolimus, whose FDA-approval status would shorten the timeline towards patient availability.

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 second part of this project we have continued to establish an optimal amount of muscle weakness in order to maximize our chance of detecting improvements with everolimus and have settled on an ideal model. With this model we have begun assessing the impact of everolimus on several different categories of tests. These are 1) the detection of DUX4 targets in the muscle in order to determine if DUX4 activity can be blocked; 2) detecting tissue damage from DUX4 expression such as cell death, inflammation and fat buildup, all features of FSHD; and 3) physical assays to determine if everolimus can improve muscle function. This included treadmill endurance and grip strength measurements. Unfortunately, no improvements in muscle damage or function has been detected so far.

Moving forward, we will continue to assess different treatment regimes and parameters to confirm the viability of Everolimus for therapy. Additionally, this work has now provided us a platform to test other FDA-approved drugs in our lab that have shown therapeutic potential in cells. By increasing the number of compounds studied, and focusing on those with FDA-approval status, we shorten the timeline towards FSHD patients ultimately having a treatment or cure.

2021-06 Report Image 1

Pipeline for Testing Therapeutic Potential of Identified Drugs. Through this project, we have established a pipeline for testing the therapeutic potential of drugs starting with our first candidate, everolimus. Initial screening was done in cells to determine if the drug can reduce cell death from DUX4 activation. Promising candidates are then moved to a DUX4 inducible mouse model to test the effect on muscle function, damage and DUX4 targets. Clinical trials will then be initiated for any successful drugs. Our goal is to focus on drugs which are already FDA-approved as it will shorten the time spent in clinical trials and thus patient availability.