FSHD is caused by production of a protein called DUX4 in skeletal muscle, that should normally be switched off, so one potential treatment for FSHD is reinstating the off state at DUX4. The protein known as SMCHD1 is normally involved in switching off DUX4 and this role is known to be critical as reduced SMCHD1 function causes FSHD2 and results in more severe disease in FSHD1. Importantly, FSHD patients retain at least some functional SMCHD1, meaning there is potential to boost the function of the remaining normal SMCHD1 so that it can again turn off DUX4. Our previous work has shown that SMCHD1 function can indeed be enhanced and in this project we will screen a 120,000-chemical library of drug-like molecules in search of chemicals that can boost SMCHD1 function. Once we have identified such molecules, we will refine their design to produce a series of molecules that could be used to develop potent drugs that activate SMCHD1 and concomitantly repress DUX4, as potential therapeutics for FSHD. These molecules will form the basis of future commercial partnerships with pharmaceutical companies. We anticipate drugs that target SMCHD1 would be used in conjunction with drugs that directly target DUX4. This project will be run at The Walter and Eliza Hall Institute of Medical Research by Associate Professor Marnie Blewitt, Dr James Murphy and Associate Professor Chris Burns.
Update July 2017
The molecule SMCHD1 has been shown to play an important role in FSHD, where it keeps the specific DNA element that causes FSHD in check, by ensuring that it goes unnoticed in the cell i.e. it is switched off. Our project is to identify drug-like chemicals that boost SMCHD1’s activity, as potential therapeutics to treat FSHD. To achieve this aim, we will screen more than 117,000 chemicals, then characterise those that enhance SMCHD1 function for how they achieve this enhanced activity and for their role in the context of living cells. In the first 6 months of the project, we have established all of the systems required to screen the large library of chemicals, and have performed a pilot screen of just over 4000 chemicals. From this pilot we have already identified 40 hits, that potentially activate SMCHD1. We are now keenly working on these molecules to validate their effect on SMCHD1, then study their interaction with SMCHD1. Alongside this preliminary work on the hits from our pilot screen, we will now screen the full library of around 113,000 chemicals, to find more such hits for future validation, with the clear aim of identifying, characterising and developing drug-like molecules that activate SMCHD1 as potential treatment for FSHD.