Translating HDAC inhibitors in Friedreich’s ataxia

ABSTRACT

Introduction: Friedreich 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.

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.

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.

KEYWORDS:

• Friedreich ataxia
• histone deacetylase inhibitor
• heterochromatin
• epigenetics
• neurodegenerative disease

Article highlights

• Friedreich ataxia is an autosomal recessive neurodegenerative disease caused by a GAA·TCC triplet expansion in the first intron of the FXN gene, encoding the essential mitochondrial protein frataxin.

• Frataxin is involved in the synthesis of iron-sulfur clusters, and transfer of Fe-S clusters to mitochondrial enzymes and components of the electron transport chain.

• Patients suffer from both neurological symptoms and cardiomyopathy due to reduced levels of frataxin protein.

• GAA·TCC repeats cause epigenetic gene silencing, reducing levels of FXN mRNA and protein, which can be reversed with histone deacetylase (HDAC) inhibitors.

• Two HDAC inhibitors have been evaluated in human clinical studies, but both molecules require improvements for use in chronic diseases.

• Medicinal chemistry efforts have revealed modifications that improve pharmacological properties of 2-aminobenzamide HDAC inhibitors, which may lead to compounds for future clinical investigation.

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Declaration of interest

JM Gottesfeld is an inventor on US patent applications 20070219244, 20110021562, 20130210918 and US Patent 8,835,502 B2 (licensees, Repligen Corporation/BioMarin Pharmaceuticals). JM Gottesfeld serves as a consultant to BioMarin Pharmaceuticals. The terms of this arrangement are managed by the Scripps Research Institute. Intellectual property has been licensed by The Scripps Research Institute to Repligen Corporation and BioMarin Pharmaceuticals, and The Scripps Research Institute and JMG have a financial interest in this technology. We wish to thank Dr. James Rusche and his associates at Repligen Corporation for their invaluable contributions to this work by taking the HDAC inhibitors into a phase Ib human clinical trial. We also thank Dr. Shripad Bhagwat and his colleagues at BioMarin for taking these compounds further toward clinical stage development. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

Studies in the Gottesfeld laboratory have been supported by grants from the National Institute of Neurological Disorders and Stroke, National Institutes of Health (R01 NS063856), the Friedreich’a Ataxia Research Alliance, GoFAR (Italy), Ataxia UK, and Friedreich’s Ataxia Society Ireland, and by a sponsored research agreement with BioMarin Pharmaceutical.