A promising gene therapy for Duchenne muscular dystrophy (DMD) improved muscle function in DMD-model rats but also revealed heart risks at high doses, suggesting the need for close heart monitoring in patients, according to a study published recently in Molecular Therapy.
The therapy, called GNT0004, uses a modified virus to deliver a shortened version of the dystrophin gene, called microdystrophin, to restore muscle strength in those with DMD.
Researchers tested GNT0004 in both healthy and DMD-model rats, administering doses up to 14 times higher than those expected for therapeutic use. At these high levels, some rats, especially those without DMD, experienced sudden deaths linked to heart rhythm problems. In contrast, the lower dose restored muscle health, normalized blood levels of creatine kinase and improved heart and skeletal muscle structure and function without major safety issues.
“[F]urther investigations are needed to elucidate the mechanisms that could be involved in the cardiac abnormalities observed in the DMD context following microdystrophin overexpression,” explained this study’s authors.
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In healthy rats, both moderate and high doses caused arrhythmias and changes to heart tissue, suggesting that too much microdystrophin may disturb normal heart protein complexes. In DMD-model rats, moderate doses were well tolerated, but higher doses still caused a few unexplained deaths and cardiac remodeling. The pattern pointed toward dose-dependent toxicity rather than an immune or inflammatory cause.
Prior toxicology studies confirmed these findings: While the standard therapeutic dose was safe, the high dose led to heart damage and metabolic changes in eight of 20 animals. These included increased heart and liver weights and microscopic signs of cardiac stress.
Despite these concerns, GNT0004 effectively reached muscle tissues, where it expressed the microdystrophin gene and improved physical performance in affected animals. Immune responses to the therapy were mild and did not interfere with its benefits. Researchers concluded that careful dose selection and heart monitoring will be critical as clinical testing progresses.
For patients with DMD, these findings highlight both hope and caution. Gene therapy may soon change the course of the disease, but the balance between restoring muscle strength and protecting the heart will be a factor in its long-term success.
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