A Korean research team has proposed a new treatment strategy that could improve treatment effectiveness for Duchenne muscular dystrophy (DMD), a rare inherited disease for which steroid treatment is the standard of care.
The team further confirmed that the EZH2 gene is also overactive in patients with DMD, which is caused by abnormalities in the dystrophin gene. This confirms the possibility of maximizing the treatment effect while minimizing side effects by combining existing steroid treatment with EZH2 inhibitors.
From left, Professors Chae Jong-hee and Choi Mu-rim and Ph. D. course student Jeon Eun-young (Courtesy of Seoul National University Hospital)
Seoul National University Hospital said Friday that Professor Chae Jong-hee of the Department of Clinical Genomics at the hospital, Professor Choi Mu-rim of the Department of Medical Science at Seoul National University College of Medicine, and Jeon Eun-young, a Ph. D. course student, analyzed muscle tissue from patients and animal models of Duchenne muscular dystrophy and identified overactivation of the EZH2 gene as a key mechanism that triggers muscle fibrosis and inflammatory responses, suggesting the possibility of new therapies to inhibit it.
Duchenne muscular dystrophy is a disease in which muscle is gradually lost due to a genetic abnormality in dystrophin production. This steel-like protein supports the walls of muscle cells. Over time, patients lose the ability to exercise, decreasing heart and respiratory function.
There are an estimated 2,000 DMD patients in Korea, mostly boys. The current treatment, steroids, has the effect of reducing inflammation, but long-term use has side effects, including muscle fibrosis, stunted growth, and weight gain, limiting its therapeutic potential.
To overcome these limitations, the research team focused on the EZH2 gene, which regulates cell proliferation and differentiation. The EZH2 gene regulates cell growth and differentiation, but it is known to impede muscle regeneration and promote fibrosis when overactive. The team hypothesized that inhibiting the activity of the EZH2 gene could improve muscle function and set out to test this theory.
The researchers performed single-nucleotide transcriptome and spatial transcriptome analyses on muscle tissue from DMD patients, patients with the milder form of Becker muscular dystrophy, and normal controls to further analyze the expression levels of the EZH2 gene and the mechanisms of muscle fibrosis. The same analysis was also performed in an animal model of DMD and compared to human patient samples.
The results confirmed that overactivation of the EZH2 gene in DMD patients and animal models is directly linked to muscle fibrosis and inflammatory responses. Using an animal model of Duchenne muscular dystrophy (D2-mdx mice), the researchers evaluated muscle tissue changes and muscle strength recovery after administration of an EZH2 inhibitor (tazemetostat) alone or in combination with a steroid (deflazacort).
The results showed that the EZH2 inhibitor alone reduced muscle fibrosis, increased muscle fiber size, and restored normal muscle morphology. In addition, compared to the steroid alone, the EZH2 inhibitor combination reduced muscle fibrosis and significantly increased muscle strength in strength tests.
The researchers added that this is an important study because it demonstrates that EZH2 inhibitors can promote muscle regeneration and improve muscle strength while minimizing the side effects of steroid treatment. This provides scientific evidence that a therapeutic strategy using EZH2 inhibitors could improve the treatment of Duchenne muscular dystrophy, a rare disease.
“Although research on the treatment of Duchenne muscular dystrophy is actively underway, there are not yet many commercially available treatments in the clinic,” Professor Chae said. “Through this study, we have discovered a new substance that enhances the effectiveness of steroid treatment, and we hope to take a step forward in treating patients through future follow-up studies.”
Professor Choi said, “In this study, we utilized patient and animal models to understand Duchenne muscular dystrophy's pathogenesis and find gene targets that can contribute to patient treatment. The results of this study have been patented, and further studies are expected to show the clinical effectiveness of EZH2 inhibitors.”
Graduate student Jeon said, “We found that drugs that inhibit the EZH2 gene can reduce muscle weakness and fibrosis while maintaining the immunosuppressive effects of steroids. This has the potential to be used not only for muscle diseases but also for various diseases that require inflammation control, and will contribute to the development of treatments based on precision medicine.”