Iron chelation therapy using deferiprone, while helping heart function, does not seem to improve neurological symptoms in Friedreich’s ataxia patients, a review study argues.
The study, “New Perspectives in Iron Chelation Therapy for the Treatment of Neurodegenerative Diseases,” was published in the journal Pharmaceuticals.
Some research suggests that an unusual iron balance, affecting the proper workings of mitochondria, play an important role in the development of neurodegenerative diseases, such as Friedreich’s ataxia. Mitochondria are the power plants of cells, producing the energy they need to function.
The combination of high iron content in areas of the brain vulnerable to neurodegeneration, and the known ability of iron to produce such damaging compounds as reactive oxygen species (ROS) and abnormal protein aggregates, likely leads to the death of affected neurons.
Researchers have also suggested that events leading to a dysfunctional high iron–ROS–mitochondrial combination are part of a self-perpetuating cycle that worsens the damage.
They propose that using iron chelators — medications that remove excess iron — in treating neurodegenerative diseases can help slow or stop the process. Several clinical trials underway are using this therapy across a range of neurodegenerative disorders.
Friedreich’s ataxia, in particular, is a disorder of iron metabolism associated with chronic inflammation and iron accumulation in the central nervous system, the myocardium (muscular tissue of the heart), and the endocrine (hormonal) system.
Pilot studies in young patients with no cardiomyopathy showed that treatment with 20-30 mg/kg/day of deferiprone, an oral iron chelator, was found to significantly decrease iron accumulation in the cerebellum (the region of the brain responsible for movement). This correlated with a reduction in neuropathy (nerve damage) and ataxic gait.
However, the effectiveness of deferiprone on neurological symptoms remains controversial. In one-year open-label extension study that followed, researchers found that deferiprone dosed at 40 mg/kg/day worsened ataxia, and results from a 20 mg/kg/day dose were inconclusive.
But researchers found that deferiprone treatment was associated with a significant reduction in cardiac hypertrophy, or an abnormal enlargement, or thickening, of the heart muscle.
A study that evaluated deferiprone given with idebenone (an antioxidant) led to an improvement in heart hypertrophy and iron deposits in the cerebellum, but with no concurrent improvement in neurological symptoms. Similar results were reported in another study, again with an improvement in heart hypertrophy.
The largest clinical trial (NCT00530127), a six-month Phase 2 study in 72 patients, evaluated treating Friedreich’s ataxia with an iron chelator at varying doses of 20, 40, or 60 mg/kg/day of deferiprone.
Safety results indicated that deferiprone was safe when administered at doses lower than 20 mg/kg/day, while the 60 mg/kg/day dose led to worsening of ataxia in two patients.
Patients receiving 20 mg/kg/day of deferiprone showed a decline in cardiac hypertrophy, but no changes in neurological symptoms. The cardiac benefit was correlated with a decrease of iron in the cardiac muscle.
In a study in 13 Friedreich’s ataxia patients, a triple therapy with deferiprone plus idebenone and riboflavin (another antioxidant) led to uncertain results. Four of the 13 stopped participating due to adverse effects and other parameters were unchanged.
Still, various studies established that a dose of deferiprone at 20 mg/kg/day appears to be safe for long-term use.
“In most trials, this treatment produced some improvement in heart function, but no improvement of the neurological symptoms were apparent. In addition, doses higher than 40 mg/kg/day seemed to worsen the disease. The effects of long-term treatment at low doses on, for example, slowing or stopping disease progression, need to be evaluated,” the researchers wrote.
“Given the multifactoriality of the neurodegenerative process, the use of multifunctional iron chelators is a promising developmental avenue,” they concluded in a discussed of iron chelation that embraced several other neurodegenerative diseases. They added that properties of future iron chelator therapy should comprise high selectivity for iron, free radical quenching capacity, mitochondrial distribution, and an ability to block protein aggregation.
But for those with Friedreich’s ataxia, they wrote, the “effects of long-term treatment at low doses on, for example, slowing or stopping disease progression, need to be evaluated.”