Researchers found a 50-year-old hypertension therapy can enhance the amount of frataxin protein in cells from patients with Friedreich’s ataxia and mouse models of the disease.
Friedreich’s ataxia is genetic disease caused by a mutation in the FXN gene. The mutations lead to reduced production of its coded protein, frataxin, which is essential for proper functioning of nerve cells and muscles.
With no effective therapies available, scientists are focused on developing new strategies to enhance frataxin production and overcome the effects of FXN mutations.
A group of Italian researchers tested whether the existing drug diazoxide could have therapeutic potential for Friedreich’s ataxia patients by increasing frataxin levels and improving the functional and biochemical features of the disease.
Diazoxide, which is sold under the brand name Proglycem, is a well-known vasodilator drug — which means it helps to relax blood vessels — that has been used for the treatment of acute hypertension for more than five decades.
The researchers started by testing the effects of diazoxide in three cell lines derived from patients with Friedreich’s ataxia. Each cell line represented a different clinical presentation of the disease — a mild, late onset case; a more common presentation; and a severe, early onset case.
After four days of treatment with diazoxide, all cell lines showed a significant changes in frataxin levels, with increases ranging from 80% to 300%.
Next, the team evaluated the activity of the drug in a mouse model of Friedreich’s ataxia. The animals received 3 mg/kg of oral diazoxide or placebo daily for up to three months. The treatment was well tolerated by the animals, and no significant adverse effects were reported.
Treated animals had a significant increase in frataxin levels compared to placebo-treated mice, with 2.6-fold and 1.6-fold increase in the cerebellum (a brain region that controls movement) and the heart, respectively.
Additional analysis revealed that diazoxide treated mice had significantly lower levels of harmful protein oxidation in the brain, pancreas, and liver tissues, with trends to decrease in other tissues.
The treatment was also found to significantly improve the coordination and footprint stride compared to placebo, but the mice still showed a generally reduced locomotor activity.
The researchers believe that these results suggest that “diazoxide is able to induce FXN expression in human cells” with therapeutic potential. Further studies are still needed to “clarify the variable effects concerning functional studies” before the drug is considered for clinical trials, the researchers stated.