Translating HDAC inhibitors in Friedreich’s ataxia

Abstract

Introduction Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by expansion of a GAA·TTC triplet in the first intron of the FXN gene, encoding the essential mitochondrial protein frataxin. Repeat expansion results in transcriptional silencing through an epigenetic mechanism, resulting in significant decreases in frataxin protein in affected individuals. Since the FXN protein coding sequence is unchanged in FRDA, an attractive therapeutic approach for this disease would be to increase transcription of pathogenic alleles with small molecules that target the silencing mechanism. Areas covered We review the evidence that histone postsynthetic modifications and heterochromatin formation are responsible for FXN gene silencing in FRDA, along with efforts to reverse silencing with drugs that target histone modifying enzymes. Chemical and pharmacological properties of histone deacetylase (HDAC) inhibitors, which reverse silencing, together with enzyme target profiles and kinetics of inhibition, are discussed. Two HDAC inhibitors have been studied in human clinical trials and the properties of these compounds are compared and contrasted. Efforts to improve on bioavailability, metabolic stability, and target activity are reviewed. Expert opinion 2-aminobenzamide class I HDAC inhibitors are attractive therapeutic small molecules for FRDA. These molecules increase FXN gene expression in human neuronal cells derived from patient induced pluripotent stem cells, and in two mouse models for the disease, as well as in circulating lymphocytes in patients treated in a phase Ib clinical trial. Medicinal chemistry efforts have identified compounds with improved brain penetration, metabolic stability and efficacy in the human neuronal cell model. A clinical candidate will soon be identified for further human testing.

Autosomal Recessive Cerebellar Ataxias: Paving the Way toward Targeted Molecular Therapies

“…Friedreich's ataxia/FA (FXN) Lack of frataxin HDCA inhibitors (109/RG833, nicotinamide) to reverse epigenetic gene silencing Herman et al, 2006;Libri et al, 2014;Soragni and Gottesfeld, 2016 Ataxia telangiectasia/AT (ATM) Lack of ATM protein Glucocorticoid induction of non-canonic splicing events in mutant ATM mRNA precursor leading to novel ATM transcripts Menotta et al, 2017 Nucleic acids influencing specific gene expression drost et al, 2011;Lynch et al, 2010;Meier et al, 2012). While modulation of mitochondrial function and attenuation of oxidative load is logical and might provide some future therapeutic option, the use of iron chelators such as deferiprone should be tested with caution as recent evidence demonstrated that depletion of mitochondrial iron further exacerbate the phenotype (Martelli et al, 2015;Pandolfo et al, 2014).…”

“…Histone deacetylase (HDAC) inhibitors reduce epigenetic silencing of genes by reverting chromatin to an open and active state for gene transcription. In preclinical studies, 2-aminobenzamide class I HDAC inhibitors were found to be the most effective to increase frataxin in patient-derived cell lines, including neuronal cells derived from patient iPSCs (induced pluripotent stem cells), and in GAA-based mouse models (Herman et al, 2006;Soragni and Gottesfeld, 2016). This led to the development of compound 109/RG833 for a phase Ib clinical trial in 20 adults with FA.…”

“…This led to the development of compound 109/RG833 for a phase Ib clinical trial in 20 adults with FA. RG833 was found to increase frataxin mRNA in circulating lymphocytes by 1.5-fold and was well tolerated (Soragni and Gottesfeld, 2016). However, as potential toxic metabolites were detected, additional compounds are currently being synthesized for further clinical development.…”

Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia

“…Other approaches tried to enhance frataxin transcription or translation. Interferon-γ (22), erythropoietin (23), or epigenetic modifiers such as histone deacetylase inhibitors (HDACis) (4,24) showed promising frataxin induction in in vitro and in vivo models, but the former 2 failed to reach endpoints in clinical trials (25,26) and the latter requires pharmacologic optimization to improve efficacy and reduce toxicity (27).…”

Exogenous and endogenous HDAC inhibitor effects in Rubinstein-Taybi syndrome models

“…For example, common interventions for these patients are behavioural support and surgical procedures for the correction of orthopaedic or cardiac malformations. In this context, exploring known drugs effects in preclinical studies is the fundamental step for envisaging therapeutic avenues (Cobos et al, 2019;Soragni and Gottesfeld, 2016). Hence, the present work explored the effects of exogenous and endogenous molecules in RSTS experimental models, that should rescue the defective enzymatic activity underlying the condition.…”