The effect of ketosis on the FRDA phenotypes
Location
Philadelphia, PA
Start Date
30-4-2025 1:00 PM
End Date
30-4-2025 4:00 PM
Description
Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease characterized by progressive gait and limb ataxia, cerebellar, pyramidal and dorsal column involvement, vision loss, scoliosis and cardiac abnormalities. The treatment option for FRDA is currently very limited. Frataxin deficiency caused OXCT1 reduction impairs ketone body metabolism and results in ketosis, however, the effect of ketosis on the FRDA phenotypes is unknown. We enhanced the OXCT1 deficiency and replicated the impact of moderate ketosis on FRDA using frataxin-deficient KIKO mice with a 50% deletion of the OXCT1 gene (KIKO Het). While OXCT1 deficiency potentiates cell death in vitro in control and FRDA patient fibroblasts, further OXCT1 deficiency in KIKO mice results in ketosis, along with increased levels of frataxin and mitochondrial biogenesis markers and improved neurobehavioral phenotypes. Furthermore, compared to KIKO mice, older KIKO Het mice (9M) showed no change in decreased frataxin and mitochondrial biogenesis markers under non-fasting conditions; however, fasting, which is known to increase ketosis levels, reversed this effect, suggesting that ketosis can increase mitochondrial biogenesis and frataxin levels. Our results thus provide ketosis-based therapy as a novel therapeutic approach for FRDA.
Embargo Period
5-19-2025
The effect of ketosis on the FRDA phenotypes
Philadelphia, PA
Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease characterized by progressive gait and limb ataxia, cerebellar, pyramidal and dorsal column involvement, vision loss, scoliosis and cardiac abnormalities. The treatment option for FRDA is currently very limited. Frataxin deficiency caused OXCT1 reduction impairs ketone body metabolism and results in ketosis, however, the effect of ketosis on the FRDA phenotypes is unknown. We enhanced the OXCT1 deficiency and replicated the impact of moderate ketosis on FRDA using frataxin-deficient KIKO mice with a 50% deletion of the OXCT1 gene (KIKO Het). While OXCT1 deficiency potentiates cell death in vitro in control and FRDA patient fibroblasts, further OXCT1 deficiency in KIKO mice results in ketosis, along with increased levels of frataxin and mitochondrial biogenesis markers and improved neurobehavioral phenotypes. Furthermore, compared to KIKO mice, older KIKO Het mice (9M) showed no change in decreased frataxin and mitochondrial biogenesis markers under non-fasting conditions; however, fasting, which is known to increase ketosis levels, reversed this effect, suggesting that ketosis can increase mitochondrial biogenesis and frataxin levels. Our results thus provide ketosis-based therapy as a novel therapeutic approach for FRDA.