When combined with microdystrophin gene therapy, trehalose improves muscle function in animal models of Duchenne muscular dystrophy (DMD), according to a study recently published in Science Advances.
Microdystrophin is a shortened yet still functional version of the dystrophin gene that can be delivered to patients to help restore muscle function. However, clinical studies have shown that the effects of microdystrophin therapy have not been as pronounced as initially hoped. This suggests that there are specific mechanisms of DMD that are not being fully targeted by the therapy.
In their study, the authors discovered that a component of cells called lysosomes are dysregulated in patients with DMD. Lysosomes are responsible for maintaining cellular function by breaking down waste.
The lysosomes of DMD mice were found to be unusually large and filled with undegraded cell material, indicating their inability to digest waste. Cells had an abnormally high number of lysosomes, as well.
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The investigators also observed signs of lysosome permeability, meaning that the lysosomal membranes may be breaking down and releasing their contents into the rest of the cell.
Next, the researchers administered microdystrophin gene therapy to mice in combination with trehalose, an FDA-approved drug that has been shown to improve lysosome function.
Findings revealed that mice receiving the combination therapy experienced significant declines in creatine kinase levels and exhibited small improvements in muscle strength. Additionally, this combination restored lysosomal function in muscle cells.
What is creatine kinase?
Creatine kinase (CK) is an enzyme found in muscles. When muscles become damaged, CK leaks out of the muscles and into the bloodstream. In diagnosing DMD, CK levels are checked in a blood sample and if they are unusually high, this is a key indicator of DMD.
“These findings highlight lysosomal damage as an important pathomechanism in DMD and suggest that combining trehalose with gene therapy could enhance therapeutic efficacy,” the authors concluded.
Future research is still needed to determine optimal doses and investigate the long-term safety and efficacy of this combination treatment, they cautioned.
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