Study of beta cells and neurons indicate incretin analogs as potential therapeutics for Friedreich’s ataxia. (S32.005)

OBJECTIVE: To investigate pathogenic mechanisms of Friedreich’s ataxia (FRDA) in relevant cellular models and identify potential therapeutics. BACKGROUND: FRDA is caused by impaired expression of frataxin, a mitochondrial protein involved in iron-sulfur (Fe-S) cluster biogenesis. We studied the consequences of frataxin deficiency and tested potential therapeutics in β-cells and neurons, two vulnerable cell types in FRDA. DESIGN/METHODS: Control and FRDA iPS cells were differentiated into neurons. Frataxin was silenced in β-cells using RNA interference. We monitored mitochondrial H2O2 production; glutathione redox state; apoptosis; expression of frataxin, Fe-S proteins, SOD2, and pro-apoptotic factors. Pro-apoptotic factors were silenced by RNA interference in β-cells. Pharmacological interventions included ROS scavengers, forskolin, and the incretin analog exendin. RESULTS: Fe-S proteins were decreased in FRDA neurons, while expression of SOD2 increased. Frataxin-silenced β-cells had increased mitochondrial H2O2 production and glutathione oxidation. Apoptosis in basal and stress conditions was higher in frataxin deficient cells. Apoptosis was due to activation of the intrinsic pathway and was reduced by ROS scavenging. β-cells induced the pro-apoptotic proteins DP5, Puma, and Bim, and decreased BAD phosphorylation. Bim was also induced in neurons. Silencing of DP5, BAD and Bim, but not Puma, reduced apoptosis. In both β-cells and neurons, treatment with the cAMP inducers forskolin and exendin, a GLP-1 agonist, normalized mitochondrial oxidative status, prevented apoptosis, and upregulated frataxin by 1.5-2 fold. Preliminary data indicate that treated FRDA neurons show increased Fe-S proteins and downregulate SOD2. CONCLUSIONS: Frataxin deficiency leads to mitochondrial oxidative stress-mediated activation of the intrinsic pathway of apoptosis in vulnerable cells. cAMP induction effectively prevents this process and also upregulates frataxin. Incretin analogs may provide a novel therapeutic strategy for FRDA. We started a proof-of-concept trial to assess if these drugs can safely induce frataxin in vivo. Study Supported by: Friedreich9s Ataxia Research Alliance, European Union 7th Framework Programme. Disclosure: Dr. Pandolfo has received personal compensation for activities with Apopharma. Dr. Pandolfo has received royalty payments from Athena Diagnostics. Dr. Pandolfo has received research support from Repligen. Dr. Igoillo-Esteve has nothing to disclose. Dr. Hu has nothing to disclose. Dr. Gurgul-Convey has nothing to disclose. Dr. Romagueira Bichara Dos Santos has nothing to disclose. Dr. Jean-Christophe has nothing to disclose. Dr. Eizirik has nothing to disclose. Dr. Cnop has nothing to disclose.