Prolonged treatment with pimelic o-aminobenzamide HDAC inhibitors ameliorates the disease phenotype of a Friedreich ataxia mouse model |
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Authors: | Sandi Chiranjeevi Pinto Ricardo Mouro Al-Mahdawi Sahar Ezzatizadeh Vahid Barnes Glenn Jones Steve Rusche James R Gottesfeld Joel M Pook Mark A |
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Institution: | a Division of Biosciences, School of Health Sciences and Social Care, Brunel University, Uxbridge, UB8 3PH, UK;b Repligen Corporation, Waltham, MA, USA;c Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA |
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Abstract: | Friedreich ataxia (FRDA) is an inherited neurodegenerative disorder caused by GAA repeat expansion within the FXN gene, leading to epigenetic changes and heterochromatin-mediated gene silencing that result in a frataxin protein deficit. Histone deacetylase (HDAC) inhibitors, including pimelic o-aminobenzamide compounds 106, 109 and 136, have previously been shown to reverse FXN gene silencing in short-term studies of FRDA patient cells and a knock-in mouse model, but the functional consequences of such therapeutic intervention have thus far not been described. We have now investigated the long-term therapeutic effects of 106, 109 and 136 in our GAA repeat expansion mutation-containing YG8R FRDA mouse model. We show that there is no overt toxicity up to 5 months of treatment and there is amelioration of the FRDA-like disease phenotype. Thus, while the neurological deficits of this model are mild, 109 and 106 both produced an improvement of motor coordination, whereas 109 and 136 produced increased locomotor activity. All three compounds increased global histone H3 and H4 acetylation of brain tissue, but only 109 significantly increased acetylation of specific histone residues at the FXN locus. Effects on FXN mRNA expression in CNS tissues were modest, but 109 significantly increased frataxin protein expression in brain tissue. 109 also produced significant increases in brain aconitase enzyme activity, together with reduction of neuronal pathology of the dorsal root ganglia (DRG). Overall, these results support further assessment of HDAC inhibitors for treatment of Friedreich ataxia. |
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Keywords: | Friedreich ataxia FRDA frataxin Trinucleotide repeat Transgenic mouse model Histone deacetylase inhibitor HDAC inhibitor |
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