Rescue of the Friedreich's ataxia knockout mouse by human YAC transgenesis

Animal and cellular models of Friedreich ataxia

“…Similarly, mouse fibroblasts cannot be sustained in culture after frataxin deletion because of the loss of cell division that leads to cell death within one week (Calmels et al 2009a). This lethal phenotype either in cells or in the whole organism can be rescued by exogenous expression of human or murine frataxin (Pook et al 2001;Calmels et al 2009a). These results are in agreement with the absence of FRDA patients identified with a complete loss of frataxin.…”

“…A second GAA repeat expansion-based mouse model has been obtained by initially crossing transgenic mice that contain the entire FXN gene within a human yeast artificial chromosome (YAC) clone onto a mouse Fxn null background, showing that transgenic human frataxin can substitute for endogenous mouse frataxin (Pook et al 2001). Then, similar YAC FXN transgenic mice were generated, but this time with a GAA repeat expansion appropriately inserted into the FXN locus, producing the YG8 line with two GAA sequences of 90 and 190 repeats and the YG22 line with one sequence of 190 repeats (Al-Mahdawi et al 2004).…”

High levels of frataxin overexpression leads to mitochondrial and cardiac toxicity in mouse models

“…Recently, using the Mck mouse, a conditional knockout (cKO) model that recapitulates most features of the FA cardiomyopathy 7 , we demonstrated that the therapeutic outcome of AAV-FXN gene therapy is directly and proportionally correlated with the vector biodistribution in the heart and that the correction of only half the cardiomyocyte was sufficient to restore fully the cardiac morphology and function 12 . In contrast to earlier reports in transgenic mouse models overexpression FXN 13,14 , several recent studies conducted in vitro 15,16 and with transgenic drosophila 17,18 have suggested that constitutive FXN overexpression could be deleterious.…”

“…>9-fold the endogenous level, is in line with previous studies conducted in yeast, mammalian cell lines, and transgenic drosophila and mice models overexpressing constitutively FXN (or Yfh1). Collectively, these studies reported dose depend toxicity when FXN overexpression was higher than 6 to 10-fold the endogenous level 15-18, 36, 37 , but good tolerance for lower levels 13,14,[38][39][40][41] . Our results also suggest that this toxicity is not generalizable to all organs and/or cell types, as the mouse liver appeared to be tolerant to FXN overexpression up to 90-fold the normal level, which is acutely toxic to the mouse heart.…”

“…Indeed, we showed previously that the functional rescue of the cardiac phenotype is achieved with as low as 50-60% of heart surface corrected 12 . It is worth noting that these mice did not display significant LV hypertrophy ( Figure S2C), but the LV diameters at the end systole (LV-ESD) and diastole (LV-EDD) appeared slightly higher in the mouse treated with 5x10 13 vg/kg and expressing 74-fold the normal level of FXN ( Figure S2D-E). Overall, these preliminary results suggested that very high level of hFXN-HA protein in cardiomyocytes could lead to impaired mitochondrial SDH enzymatic activity but without notable iron accumulation.…”