Emerging therapeutics for the treatment of Friedreich’s ataxia

ABSTRACT

Introduction: Friedreich ataxia (FRDA) is an autosomal recessive disorder which manifests with progressive instability, leading ultimately to loss of independent gait, dysarthria, skeletal abnormalities and cardiomyopathy. FRDA is caused in 96% of cases by a GAA repeat expansion in the first intron of FXN gene. Pathologic GAA expansions hinder transcriptional activity and result in a reduced expression of the mitochondrial protein frataxin. At a cellular level, frataxin deficiency is accompanied by impaired oxidative phosphorylation, mitochondrial biogenesis and abnormal iron trafficking. From the discovery of disease causing mutation in 1996, combined efforts in basic and clinical research led to the investigation of several potential therapeutic compounds which intervene in different steps of the pathogenetic cascade.

Areas covered: In the present review we aimed to critically reappraise current findings from clinical trials in FRDA, including an overview on trial design and preliminary data from ongoing studies.

Expert opinion: Despite the several trials finalized in the past years, no therapeutic is currently available for the treatment of FRDA. A number of promising compounds failed to show a significant effect when shifted in a randomized, placebo-controlled setting, because of missing natural history data, poor study design or insufficient preclinical evidence.

KEYWORDS:

• Antioxidants
• clinical trials
• frataxin upregulation
• Friedreich´s ataxia

Article highlights

• Friedreich ataxia (FRDA) is a genetic disorder which manifests with progressive gait instability, dysarthria, skeletal abnormalities and cardiomyopathy.

• The pathophysiology of FRDA depends upon a reduced synthesis of frataxin which results in impaired oxidative phosphorylation, mitochondrial biogenesis and abnormal iron trafficking in the cell.

• Explored therapeutic strategies target multiple steps of the pathogenetic cascade in FRDA and include antioxidants, iron chelator, enhancer of mitochondrial function and epigenetic modifiers.

• Apart from symptomatic treatment options, new promising strategies, such as antisense oligonucleotide and gene therapy are currently tested in different FRDA disease models.

• Recently, large natural history studies provided excellent data on the course of disease which allows accurate sample calculation. This will possibly enable to design sufficiently powered future studies in FRDA.

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Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. A reviewer on this manuscript has disclosed as being one of the PIs of many of the trials discussed. A reviewer on this manuscript has disclosed their laboratory is engaged in development of HDAC inhibitors as therapeutics for Friedreich’s ataxia and that they collaborate with BioMarin Pharmaceutical and in this capacity the reviewer serves as a paid consultant to BioMarin.

Additional information

Funding

This paper is not funded.