Existing treatments may help fight symptoms of severe form of muscular dystrophy, new research suggests

(Press-News.org) A new study led by researchers at Hospital for Special Surgery (HSS) suggests that currently available therapies may help control chronic muscle inflammation in Duchenne muscular dystrophy (DMD), a severe condition that leads to muscle weakness and premature death. The study, published in PNAS, identifies new mechanisms that drive chronic muscle inflammation in a disease model of a DMD. Researchers believe that targeting these mechanisms with existing therapies could help reduce inflammation and support muscle function.

DMD is caused by a mutation in the dystrophin gene, which produces a large protein essential for stabilizing muscle cell membranes that help protect muscle fibers. Without dystrophin, muscle damage occurs and builds, leading to persistent inflammation and fibrosis (scarring). The condition primarily affects boys—occurring in about 1 in 5,000 live male births—and leads to premature death due to respiratory and cardiac muscle weakness. There is currently no cure.

The research team focused on monocytes (a type of white blood cell) that travel through the blood stream to infiltrate diseased muscles and become inflammatory macrophages, which promote muscle damage and scarring. They previously discovered that blocking monocyte recruitment from the blood circulation temporarily decreased macrophage accumulation, reduced scarring, and improved muscle function in a disease model of DMD.

“The benefit is transient,” says Lan Zhou, MD, Neurologist-in-Chief at HSS and senior author of the study. “Inhibiting macrophage infiltration alone is not sufficient for controlling chronic muscle inflammation, which contributes to muscle damage and fibrosis,”

To uncover additional factors driving macrophage accumulation, the investigators used state-of-the-art technologies, including single-cell RNA sequencing analysis and lineage tracing, to determine the key mechanism that is responsible for fueling chronic inflammation after macrophage infiltration is blocked.

According to the newly published research, Dr. Zhou and her colleagues discovered that mesenchymal stromal cells (a type of stem cell) in muscle tissue called fibro/adipogenic progenitors (FAPs) produce cytokines or growth factors known as colony-stimulating factor (CSF-1). CSF-1 stimulates resident macrophages in skeletal muscles to proliferate and accumulate, which contributes to chronic inflammation and muscle dystrophy. The findings uncover a new function of FAPs that fuels chronic inflammation and promotes DMD disease progression.

The researchers concluded that it might be equally important to suppress resident macrophage expansion and activation in addition to inhibiting macrophage infiltration.

“That means that in order to control chronic muscle inflammation and improve muscle function in patients with DMD, both macrophages and FAPs may need to be targeted,” explains Dr. Zhou.

As a next step, Dr. Zhou and her team are planning to study the safety and efficacy of a combination therapy using two existing drugs developed for other conditions. One is used to treat chronic inflammation by suppressing macrophage infiltration. The other is a CSF-1 inhibitor used to treat a type of joint tumor that consists of many macrophages due to excessive CSF-1. 

Limited treatment options exist for patients with DMD. Researchers continue to refine gene therapy and cell therapy approaches for DMD, which have so far shown limited success in clinical trials.

“Experts in the field believe that patients will ultimately require a combination of treatment approaches, not only to correct genetic defects, but also to improve the diseased muscle tissue environment, making the gene and cell therapies more effective,” says Dr. Zhou. “Targeted drugs could be used to treat the inflammatory and fibrotic tissue environment so that healthy genes or cells can be efficiently engrafted, survive, and function.”

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