Building tools to accelerate drug development and clinical trials
In the pioneering days of the Society, all our research funding went to basic research aimed at discovering the genetic cause of FSHD and advancing understanding of the disease itself. We have moved into a new era with many ideas for therapies (which would not have happened without our early efforts). Appropriately, funding has shifted into research aimed at developing more effective therapies and improving the design of clinical trials.
Tools to aid drug development
FSHD is difficult to study in the research lab, so there is an ongoing need for better tools. For example, because human DUX4 is different from the mouse version, scientists have had to use clever tricks to get human DUX4 into mice and cause FSHD-like features in mice. Such animals are valuable for testing new ideas for therapy, but they come with pitfalls because of the differences between mouse and human. To get around this, a scientist we funded is creating a mouse using additional human components of the DUX4 genetic machinery. If his efforts result in a good model, it will be a valuable addition to the toolbox for drug development.
Many up-and-coming candidate therapies for FSHD are based on molecules designed to block or destroy DUX4 messenger RNA (mRNA). This would make the DUX4 gene unable to exert its toxic effects. Getting these therapeutic molecules to work in a test tube is one thing. Getting these molecules to reach every muscle in the body and to work their way inside each muscle cell presents a whole other level of difficulty. Several groups funded by the Society are engineering new and innovative methods to deliver these molecules preferentially to skeletal muscle.
Tools for clinical trials
We have also funded several studies to develop blood biomarkers, collaborating with academic researchers and companies to speed up the process. Blood biomarkers are molecules that might migrate out of skeletal muscle as part of the disease process and circulate in the bloodstream. For example, a well-known biomarker is blood creatine kinase as an indicator of the muscle damage and can be elevated following high cholesterol drugs, such as statins.
In FSHD, the idea is that if a muscle somewhere in the body is expressing DUX4, it should be possible to detect this through a blood test. Unfortunately, because DUX4 expression occurs rarely, unpredictably, and at very low levels, it’s not feasible to look for DUX4 directly. Instead, one can search for a distinctive set of other proteins triggered by DUX4. The challenge is that the “noise” of unrelated proteins floating around in the blood is much louder than the faint whisper of FSHD-triggered proteins. We have funded studies to explore whether these proteins can be detected using a highly sensitive tool call mass spectrometry.
Muscle function (aka “clinical outcome”) is also important to measure in a clinical trial because, ultimately, a treatment needs to benefit patients in their daily activities. Research on clinical outcomes for muscular dystrophies has focused on tasks like walking, lifting objects, standing up, etc. But many people with FSHD have mentioned the loss of facial expression as one of the more devastating aspects of their condition. Yet there are no validated tools to measure changes in facial muscles in FSHD patients, so we have funded a grant that aims to develop such methods.
Another project is piloting the use of artificial intelligence (AI) to comb through data from the U.S. national registry to search for characteristics of patients that correlate with a faster progression of symptoms. Such insights could be useful for designing eligibility criteria for clinical trials, as it should be easier to detect positive drug benefits in a group of patients who are likely to progress faster.