In several murine models of Friedreich ataxia (FA), inducing continuous, but not intermittent, hypoxia regimens has been shown to prevent ataxia and neurologic disease, according to findings from a study published in Human Molecular Genetics.
FA is a neurodegenerative, multisystemic disorder that presents at between 5 and 20 years of age, predominantly with progressive spinocerebellar and sensory ataxia. Patients with the disease can develop additional symptoms as well, such as diabetes, hypertrophic cardiomyopathy, and scoliosis. Although the neurologic manifestations of the disease are the most debilitating, the leading cause of death is ultimately cardiac dysfunction at a median age of 37.5 years.
The researchers of the current analysis previously demonstrated that oxygen is a “potent environmental modulator of FA in several model systems,” having specifically shown that hypoxia preserves iron sulfur cluster concentrations and thus tackling the primary deficiency in FA. Further, they revealed that the continuous, chronic treatment of short hairpin RNA targeting frataxin (shFxn) mice with 11% oxygen could prevent the onset of ataxia and neurologic disease.
The current study was designed as a preclinical evaluation of 7 hypoxia-inspired regimens in shFxn mouse models of FA. The long-term goal of the researchers was to design more practical, effective regimens for clinical translation that harness the power of hypoxia. They noted that an important consideration for any future regimen was to determine the safety of all the regimens that underwent analysis.
Read more about experimental therapies for FA
There were 3 key findings from the study:
- A daily intermittent hypoxia regimen, which involved 16 hours of 11% oxygen and 8 hours of 21% oxygen, was not associated with any benefits. In fact, this treatment was actually harmful, leading to elevated cardiac stress and accelerated mortality. These detrimental effects were due most likely to transient tissue hyperoxia, which is associated with daily exposure to 21% oxygen combined with chronic polycythemia.
- Milder regimens of chronic hypoxia, involving 17% oxygen, are associated with modest benefits, as observed with delays in the onset of ataxia.
- The initiation of chronic, continuous 11% oxygen breathing late in the FA disease process—that is, once advanced neurologic disease has already commenced—can reverse ataxia in a rapid fashion.
“Our studies showcase both the promise and limitations of candidate hypoxia-inspired regimens for FA and underscore the need for additional preclinical optimization before future translation into humans,” the researchers concluded.
Reference
Ast T, Wang H, Marutani E, et al. Continuous, but not intermittent, regimens of hypoxia prevent and reverse ataxia in a murine model of Friedreich’s ataxia. Hum Mol Genet. Published online June 1, 2023. doi:10.1093/hmg/ddad091
