Ast T, Wang H, Marutani E, Nagashima F, Malhotra R, Ichinose F, Mootha VK.
The authors previously reported that oxygen is a key environmental variable that can modify FA pathogenesis. In particular they showed that chronic, continuous normobaric hypoxia (11% FIO2) prevents ataxia and neurological disease in a murine model of FA, although it did not improve cardiovascular pathology or lifespan. This study reports the pre-clinical evaluation of seven 'hypoxia-inspired' regimens in the shFxn mouse model of FA, with the long-term goal of designing a safe, practical, and effective regimen for clinical translation. Three chief results are reported. First, a daily, intermittent hypoxia regimen (16 hours 11% O2/8 hours 21% O2) conferred no benefit, and was in fact harmful, resulting in elevated cardiac stress and accelerated mortality. The detrimental effect of this regimen is likely due to transient tissue hyperoxia that results when daily exposure to 21% O2 combines with chronic polycythemia, as this toxicity could be blunted by pharmacologically inhibiting polycythemia. Second, more mild regimens of chronic hypoxia (17% O2) confers a modest benefit by delaying the onset of ataxia. Third, excitingly, initiating chronic, continuous 11% O2 breathing once advanced neurological disease has already started can rapidly reverse ataxia. These studies showcase both the promise and limitations of candidate hypoxia-inspired regimens for FA and underscore the need for additional pre-clinical optimization before future translation into humans.
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