Adding a temporal dimension to the study of Friedreich's ataxia: the effect of frataxin overexpression in a human cell model

Tommaso Vannocci, Roberto Notario Manzano, Ombretta Beccalli, Barbara Bettegazzi, Fabio Grohovaz, Gianfelice Cinque, Antonio de Riso, Luca Quaroni, Franca Codazzi, Annalisa Pastore
Disease Models & Mechanisms 2018 : dmm.032706 doi: 10.1242/dmm.032706 Published 24 May 2018

We prove that overexpression of the frataxin gene affects the cellular metabolism. It also lead to a significant increase of oxidative stress and labile iron pool levels. These cellular alterations are similar to those observed when the gene is partially silenced, as it occurs in Friedreich's ataxia's patients. Our data suggest that the levels of frataxin must be tightly regulated and fine-tuned, any imbalance leading to oxidative stress and toxicity.
Viral approaches (AAV), take advantage of a human exogenous FXN gene under the control of strong promoters that induce overexpression of the therapeutic genes. Although the mouse models showed great improvements, the lack of a tight control on the levels of expression could generate the effects detailed in this work with unknown long-term consequences for patients treated this way. Recent studies have taken advantage of the novel CRISPR gene editing approach to produce the desired gene correction as an alternative, gene correction of the endogenous FXN gene by reduction of the GAA expansion seems to be preferable. This strategy has the advantage that frataxin levels would be restored to physiological levels. It is however essential for these studies to determine the effects of different levels of frataxin.

Adding a temporal dimension to the study of Friedreich's ataxia: the effect of frataxin overexpression in a human cell model