New frontiers in muscle regeneration for FSHD

Once seen as a long shot, now more companies are looking at strategies to regrow muscles

by Jamshid Arjomand, PhD, Chief Science Officer

Over the past few years, there has been an increase in the number of pharmaceutical companies developing FSHD therapeutics. These strategies primarily focus on blocking DUX4, the toxic element that causes FSHD. These treatments are considered “disease modifying” because they target the root cause of the disease, and if effective, would stop the disease from progressing and becoming more debilitating.

People with FSHD have testified that stopping the disease from progressing is the highest priority. But for the next generation of therapies, strategies are being developed to address the loss of muscle tissue and function. Although this goal was once considered a long shot, there are now several approaches that aim to increase and possibly recover loss of muscle mass, which, if paired with disease-modifying drugs, could in turn reverse the impact of FSHD.

One of these approaches is to boost growth of the existing muscle. This should increase strength and extend functional use of the muscle over the course of the disease. There have already been several trials for this approach in FSHD which have generated mixed results. These include a trial of MYO- 029 by Wyeth Pharmaceuticals in 20082 and of ACE-083 by Acceleron Pharmaceuticals that concluded in 2019.

While both approaches were deemed safe and showed signs of muscle growth, they failed to show enhanced functional outcomes and were discontinued. However, these trials paved the way for the design of better clinical trials, and in the coming year, Roche Pharmaceuticals will make use of these important findings as they launch a Phase 2 clinical trial for their drug, RO7204239, to promote muscle growth.

In FSHD (and many other muscle conditions), the skeletal muscle gets replaced with fat and scar tissue. This can hinder muscles from rebuilding and contribute to loss of strength. This fat infiltration and scarring is believed to be driven by the immune system. In normal conditions, the immune system helps to maintain healthy muscles. But in FSHD, the constant damage to muscle may over-activate the immune system and release signals that promote scarring and fat infiltration.

Recent FSHD Society grants (for example to Yegor Vassetzky & Carlo Serra) have invested in basic research to better characterize the type of immune cells and signaling that contribute to fat infiltration and scarring. This work is still in its early days, but as our understanding of these processes grows, new therapeutic strategies can be developed to block fat infiltration and scarring, and promote healthy muscle regeneration.

Lastly, stem cell therapies are another burgeoning area of research. Most recently, the laboratories of Michael Kyba and Rita Perlingeiro at the University of Minnesota published a study in which mouse stem cells were used to replace the muscle loss in an FSHD mouse model.

Although this technique is early in its development, the study highlights the potential for this type of approach and the use of stem cell therapies to rebuild skeletal muscle. At the forefront of this work is the team from Vita Therapeutics, a Maryland-based biotech company that is developing human stem cell replacement strategies to correct and replace damaged muscles for limb girdle muscular dystrophy and FSHD.

All of these innovative regenerative approaches are being developed in concert with disease-modifying therapies to promote a more holistic treatment for FSHD and other neuromuscular indications. The goal is not just to stop disease progression, but to find treatments that can someday reverse the damage and restore functions that have been lost.