Dimethyl fumarate, an approved therapy for multiple sclerosis (MS), may help people with Friedreich’s ataxia by increasing the amount of frataxin protein that is deficient in these patients, an international research team has found.
This suggests that the treatment may help overcome the metabolic impairment characteristic of Friedreich’s ataxia and improve the outcomes of those affected by this rare disease.
These findings were reported in a study, “Dimethyl fumarate dosing in humans increases frataxin expression: A potential therapy for Friedreich’s Ataxia,” which was published in the journal Plos One.
Friedreich’s ataxia is a genetic disease caused by the expansion of a small DNA sequence or point mutations on the FXN gene. This leads to the production of abnormally large and non-functional frataxin proteins or impaired production of the normal version of the protein.
Although the molecular role of frataxin remains poorly understood, its loss can cause speaking difficulties, movement and heart problems, as well as serious spine and feet deformities, among other symptoms.
To overcome the molecular hallmark feature of Friedreich’s ataxia, researchers have been focused on finding safe and effective ways to increase the amount of functional frataxin protein.
A team led by researchers from University of California, Davis, showed that treatment with the approved MS therapy dimethyl fumarate, marketed as Tecfidera by Biogen, could be a potential strategy to treat patients with Friedreich’s ataxia.
Dimethyl fumarate was designed to target a protein called Nrf2, in turn boosting the activity and number of mitochondria (cells’ powerhouses), and the production of antioxidant factors.
The team analyzed the levels of frataxin protein in 14 patients with MS upon three months of treatment with Tecfidera. They found that the amount of the coding FXN gene was increased by 85.1% compared to before the treatment.
Moreover, the team evaluated the impact of dimethyl fumarate on cellular and animal models of this rare disease.
The researchers found that treatment with dimethyl fumarate could induce the production of frataxin in patient-derived cells cultured in the lab, even in the presence of the FXN expansion mutations. Also, treatment with 10 mg/kg of dimethyl fumarate could induce the production of frataxin up to 52% in cells of the cerebellum — a brain region that is most affected in Friedreich’s ataxia — of mice with the disease.
“There is a positive co-relation between Friedreich’s ataxia patient and frataxin level in the blood to age of disease onset,” the researchers wrote. So, they believe that “this modest increase in frataxin is highly clinically relevant as increase (…) by ~80% has potential to delay the age of [disease] onset by many years.”
Further analysis also revealed that the treatment could enhance the production of mitochondria by 76% in patient-derived cells, which could help support the high energy expenditure of nerve cells in these patients.
To date, more than 200,000 patients with MS and psoriasis have been treated with dimethyl fumarate, which has demonstrated that it is a safe and well-tolerated therapy.
These preclinical results, together with the therapy’s good safety profile, support its potential therapeutic use to help overcome the underlying molecular features of Friedreich’s ataxia, the researchers said.
“Since inherited deficiency in frataxin is the primary cause of Friedreich’s ataxia, and dimethyl fumarate is demonstrated to increase FXN expression in humans, dimethyl fumarate could be considered for Friedreich’s therapy,” they concluded.