2 Compounds Targeting Oxidative Stress Prevent CMT Symptoms in Mice
Two approved compounds, the antibiotic florfenicol or the MitoQ antioxidant supplement, prevented symptom development in a mouse model of Charcot-Marie-Tooth disease (CMT) caused by mutations in the GDAP1 gene, a study shows.
Notably, these benefits were associated with a reduction in oxidative stress, an imbalance between the production of potentially harmful reactive oxygen species (ROS) and a cell’s ability to detoxify them with antioxidants, causing cell and tissue damage.
Study findings highlight oxidative stress as an important contributor to GDAP1-associated CMT, such as types 4A and 2K, and support opening clinical trials into whether these commercially available compounds can be repurposed to treat CMT, the researchers noted.
The study, “Effective therapeutic strategies in a pre-clinical mouse model of Charcot–Marie–tooth disease,” was published in the journal Human Molecular Genetics.
Repurposing compounds approved for one disorder to treat another helps to “overcome the millionaire costs and decade-long tasks” needed to develop a safe and effective treatment. Such efforts are particularly relevant for rare diseases, “where pharmaceutical investments are scant,” the researchers wrote.
A team of researchers in Spain applied this strategy to treating CMT caused by GDAP1 mutations, which have been shown to impair mitochondrial function and promote oxidative stress.
Problems in mitochondria, the cell’s powerhouses, can boost the production of ROS, thereby increasing oxidative stress.
As such, the researchers looked for agents supporting mitochondrial function among 1,018 U.S.-approved small compounds.
After a series of tests in lab-grown human cells with or without the GDAP1 gene, the researchers identified florfenicol, methylthiouracil, and isosorbide as the best candidates, whose potential was further evaluated in nerve cells from a mouse model of GDAP1-associated CMT.
Florfenicol is a broad-spectrum antibiotic mainly used in veterinary medicine, methylthiouracil was originally introduced to suppress an overactivated thyroid, and isosorbide to control heart disease.
Only florfenicol was found to significantly boost mitochondrial function in nerve cells from the mouse model, compared with cells from healthy mice, suggesting that it could be a potential treatment for GDAP1-associated CMT.
Further analysis revealed that the antibiotic significantly reduced mitochondria-associated ROS production to comparable levels obtained with MitoQ, a mitochondria-targeted antioxidant sold as a dietary supplement.
While florfenicol treatment failed to lessen disease severity in the mouse model when given after symptom onset, it effectively prevented disease-associated weight gain and motor deficits when started before the appearance of symptoms.
Similar results were observed when the mice were treated with MitoQ since early life (before symptom onset).
Additional analysis showed that the levels of enzymes involved in energy-producing mitochondrial functions and in antioxidant response were significantly reduced in the peripheral sciatic nerves (the longest nerve in the body) of the CMT mouse model, compared with those of healthy mice.
Importantly, treatment with either florfenicol or MitoQ increased the levels of these enzymes and partly lessened oxidative damage in the sciatic nerves.
These findings support oxidative stress as a key contributor of CMT-associated nerve damage and indicate that both florfenicol and MitoQ prevent CMT development “by ameliorating the dysfunction of energy metabolism and [oxidative damage] in peripheral nerves of a mouse model of CMT disease,” the researchers wrote.
As such, these two compounds have the potential to be repurposed for the treatment of GDAP1-associated CMT and other types associated with excessive ROS production, such as CMT type 2A.