Restoring Expression of Frataxin May Halt FA Progression, Improve Symptoms

Treating nerve cells derived from Friedreich’s ataxia (FA) patients with a molecule called compound 109 significantly increases the expression of the frataxin gene and protects them from cell death induced by oxidative stress, suggests a study published in the scientific journal Human Molecular Genetics.

Compound 109 cannot be directly used as a drug to treat FA due to its poor penetration into the brain and potential toxicity for the heart. But the development of compounds sharing the same activity as compound 109 without such liabilities may provide promising potential treatments for FA, according to the study, “Friedreich ataxia-induced pluripotent stem cell-derived neurons show a cellular phenotype that is corrected by a benzamide HDAC inhibitor”.

“Our findings support frataxin restoration as the key approach for therapeutic intervention in [FA],” the researchers wrote. They added that restoring the expression of frataxin may not only halt disease progression but also improve FA symptoms.

In order to describe the changes associated with the lack of frataxin, the team of researchers led by Dr. Massimo Pandolfo at Belgium’s Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles, obtained skin cells from people with FA and healthy volunteers. They then transformed these cells into undifferentiated stem cells — also called induced pluripotent stem cells (iPSC) — that are able to produce different cell types including nerve cells. The skin cells obtained from FA patients lacked frataxin, while those obtained from healthy controls did not.

Although the iPSC derived from FA skin cells were equally capable of dividing into nerve cells, there were several differences between these cells and healthy cells. For instance, nerve cells derived from FA iPSCs showed a signature of high oxidative stress and therefore were more sensitive to oxidants compared to nerve cells derived from normal skin cells.

The scientists then wanted to see whether up-regulating the expression of frataxin in the FA cells could restore the alterations linked to the lack of frataxin. To this end, they treated the FA-derived nerve cells with compound 109, which significantly reduced oxidative stress and almost fully protected FA neurons from cell death caused by oxidative stress.

“Our findings suggest that correction of frataxin deficiency may not only stop disease progression,  but also lead to clinical improvement by rescuing still surviving, but dysfunctional, neurons,” the authors concluded.