A new preclinical study has shown that Setanaxib, an inhibitor of the oxidative stress enzymes NOX1 and NOX4, preserved cardiac function and reduced fibrosis in two models of Duchenne muscular dystrophy.
Researchers at the University of South Florida (USF) Health Morsani College of Medicine have identified a potential new way to protect heart function in people with Duchenne muscular dystrophy (DMD).
The findings show that the experimental drug Setanaxib helped preserve cardiac function, reduce heart enlargement and limit tissue scarring in two preclinical models of DMD. The research also identified an enzyme known as NOX4 as a potential target for future treatments aimed at preventing cardiomyopathy, a leading cause of death among people living with the condition.
DMD is a rare inherited genetic disorder that primarily affects boys because it is linked to the X chromosome. It is caused by mutations that prevent the production of functional dystrophin, a protein that protects and stabilises muscle cells. Without it, muscles become damaged over time, with healthy tissue gradually replaced by fat and scar tissue.
While the disease is best known for causing progressive muscle weakness, damage to the heart becomes more prominent as patients live longer thanks to advances in treatment.
Targeting oxidative stress
The study was led by Da-Zhi Wang, Professor at the USF Health Morsani College of Medicine and Director of the Center for Regenerative Medicine at the USF Health Heart Institute. The research team also included Associate Professor John Mably, Assistant Professor Gabriela Diniz and collaborators from other institutions.
Together, they looked at Setanaxib, an experimental drug designed to reduce oxidative stress. The drug works by targeting the enzymes NOX1 and NOX4, which produce reactive molecules that play important roles in normal cell function but can become harmful when produced in excess.
In the study, treatment with Setanaxib preserved the heart’s ability to pump blood while reducing inflammation, fibrosis and the activity of genes associated with cardiomyopathy. The findings suggest that blocking this biological pathway could help slow the progression of heart disease linked to DMD.
“Despite great progress in the development of gene replacement therapies, Duchenne muscular dystrophy remains a devastating disease,’’ Wang said. “Understanding the causes of DMD progression is urgently needed to advance therapies that alleviate symptoms and improving quality of life.”
Building on years of research
The findings build on more than 15 years of DMD research carried out in Wang’s laboratory, where scientists have focused on understanding how the disease develops and identifying biological mechanisms that could lead to new treatments.
“The results are very promising,” Mably said. “The Nox4 inhibitor has already been tested in clinical trials for the treatment of lung fibrosis and kidney and liver disease. We hope it will also be tested soon in clinical trials in DMD patients to slow the progression of heart disease.’’
Although further research and human clinical trials will be needed before the treatment could become available, the researchers believe the study represents an important advance in understanding the mechanisms behind DMD-related heart disease.
“Our new study represents an important step forward for the field and for our cardiac and regenerative medicine program,” Diniz said. “It shows how efforts in basic biomedical sciences are crucial for understanding human disease and health care advancements.”
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