Table 2 Studies utilising FRDA iPSCs and their derived models to investigate pharmacological approaches to FRDA therapy
Therapeutic strategy | Drug(s) | Study | Year | Drug class | Cell type(s) utilised | Study outcome |
|---|---|---|---|---|---|---|
Pharmacological inhibition of epigenetic machinery | HDACi 109/RG2833 | Soragni et al. [42] | 2014 | HDAC inhibitor | FRDA iPSC-derived neurons | HDAC inhibition by 5 µM of HDACi 109 upregulates FXN mRNA levels by approximately 2.5 folds in FRDA neurons |
HDACi 109 HDACi 966 HDACi 233 | Soragni et al. [43] | 2015 | HDAC inhibitor | FRDA iPSC-derived neurons | Inhibition of both HDAC1 and HDAC3 is required for FXN activation. Only compounds targeting these HDACs are active in increasing FXN mRNA | |
HDACi 109/RG2833 | Codazzi et al. [44] | 2016 | HDAC inhibitor | FRDA iPSC-derived neurons | Significant increase in frataxin protein levels with no effect in neurons derived from healthy individuals | |
Sodium butyrate (NaB) Tranylcypromine (Parnate) | Polak et al. [45] | 2016 | HDAC inhibitor Histone demethylase inhibitor (KDM1A inhibitor) | FRDA iPSCs | Both compounds correct some of the repressive histone modifications at the FXN locus exclusively in FRDA iPSCs and significantly increase FXN expression | |
HDACi 109/RG2833 | Hu et al. [46] | 2017 | HDAC inhibitor | FRDA iPSC-derived primary sensory neurons | FRDA PSNs treated with 5 µM of HDACi 109 resulted in a significant increase in both FXN mRNA and protein levels with no effect in control cells | |
HDACi 109/RG2833 | Lai et al. [47] | 2019 | HDAC inhibitor | FRDA iPSC-derived neurons FRDA iPSC-derived isogenic sensory neurons | HDACi treatment partially restores some cellular pathways affected by the loss of FXN. Those include neuronal function, regulation of transcription, extracellular matrix organization, and apoptosis | |
Resveratrol Nicotinamide | Georges et al. [48] | 2019 | HDAC inhibitor | FRDA iPSC-derived neurons | Resveratrol and nicotinamide do not increase FXN expression in iPSC-derived neurons as they do on fibroblasts and lymphoblastoid cells | |
CI994 Entinostat Mocetinostat | Schreiber et al. [49] | 2022 | HDAC inhibitor | FRDA iPSC-derived neural progenitor cells FRDA iPSC-derived neurons | Treatment with CI994, Entinostat and Mocetinostat increased FXN mRNA and protein levels in FRDA iPSC-derived NPCs and terminally differentiated neurons | |
DNA sequence-specific polyamides therapy | Polyamide FA1 | Du et al. [19] | 2012 | β-alanine-linked polyamides | FRDAA iPSCs | FA1 partially blocks repeat expansion by displacing the mismatch repair enzyme MSH2 from intron 1 of FXN |
GAA-specific polyamide FA1 | Gerhardt et al. [50] | 2016 | β-alanine-linked polyamides | FRDA iPSC-derived neurons | FA1 polyamide releases the replication fork stalling and alleviates expansion of the GAA repeats | |
Iron-homeostasis modulation | Idebenone (IDE) Deferiprone (DFP) | Lee et al. [51] | 2016 | Antioxidant coenzyme Q10 analogues (IDE) Iron chelators (DFP) | FRDA iPSC-derived cardiomyocytes | DFP modulates iron homeostasis and effectively relieves stress stimulation related to cardiomyopathy. DFP was also shown to be more effective than IDE for treating FRDA-mediated cardiomyopathy |
Sequence-specific synthetic transcription elongation factor (Syn-TEFs) therapy | Syn-TEF1 Syn-TEF2 | Erwin et al. [52] | 2017 | Syn-TEFs | FRDA iPSCs FRDA iPSC-derived neurons & cardiomyocytes | Syn-TEF1 stimulates the production of mature FXN protein by actively assisting RNA Pol II with productive elongation |
Incretin receptor treatment | Forskolin Exenatide [D-Ala2]-GIP | 2020 | GLP-1 analogues | FRDA iPSC-derived sensory neurons FRDA iPSC-derived  β cells | All 3 compounds increased frataxin protein expression in FRDA iPSC-derived neurons. Both Forskolin and exenatide decreased oxidative stress and inhibited the mitochondrial pathway of apoptosis. Exenatide was also shown to improve mitochondrial function | |
FXN-mRNA stabilisation | Antisense oligonucleotides targeting FXN mRNA | Li et al. [53] | 2021 | Antisense oligonucleotides | FRDA iPSC-derived neural progenitor cells | Electroporation-mediated delivery of FXN mRNA-targeting oligonucleotides increased FXN mRNA expression in FRDA iPSC-derived neural progenitor cells |