Emerging therapies in Friedreich’s Ataxia

ABSTRACT

Introduction

Friedreich’s ataxia (FRDA) is a progressive, neurodegenerative disease that results in gait and limb ataxia, diabetes, cardiac hypertrophy, and scoliosis. At the cellular level, FRDA results in the deficiency of frataxin, a mitochondrial protein that plays a vital role in iron homeostasis and amelioration of oxidative stress. No cure currently exists for FRDA, but exciting therapeutic developments which target different parts of the pathological cascade are on the horizon.

Areas covered

Areas covered include past and emerging therapies for FRDA, including antioxidants and mitochondrial-related agents, nuclear factor erythroid-derived 2-related factor 2 (Nrf2) activators, deuterated polyunsaturated fatty acids, iron chelators, histone deacetylase (HDAC) inhibitors, trans-activator of transcription (TAT)-frataxin, interferon gamma (IFNγ), erythropoietin, resveratrol, gene therapy, and anti-sense oligonucleotides (ASOs), among others.

Expert opinion

While drug discovery has been challenging, new and exciting prospective treatments for FRDA are currently on the horizon, including pharmaceutical agents and gene therapy. Agents that enhance mitochondrial function, such as Nrf2 activators, dPUFAs and catalytic antioxidants, as well as novel methods of frataxin augmentation and genetic modulation will hopefully provide treatment for this devastating disease.

KEYWORDS:

• Friedreich’s Ataxia
• treatment
• antioxidants
• gene Therapy
• epi-743
• tat-Frataxin
• omaveloxolone

Article highlights

• Friedreich’s Ataxia (FRDA) is a neurodegenerative disease affecting children and young adults. It is the most common form of autosomal recessive ataxia.

• FRDA causes a marked reduction of ‘frataxin,’ a mitochondrial protein that plays a vital role in iron homeostasis and mitigation of damaging oxidative stress.

• There is neither a treatment nor a cure for FRDA. Nevertheless, new and exciting prospective treatments for FRDA are currently on the horizon.

• Pharmacological agents that improve mitochondrial function, such as antioxidants and nuclear factor erythroid-derived 2-related factor 2 (Nrf2) activators, are being evaluated as potential treatments of FRDA.

Novel ways of increasing frataxin are also being researched, including HIV-Trans-activator of Transcription (TAT) frataxin–a carrier molecule used to deliver frataxin into the mitochondrial matrix–, gene therapy using adeno-associated virus (AAV vectors), and genomic editing.

Declaration of interest

TA Zesiewicz has received personal compensation for serving on the advisory boards of Boston Scientific; Reata Pharmaceuticals, Inc; and Steminent Biotherapeutics. TA Zesiewicz has received personal compensation as senior editor for Neurodegenerative Disease Management and as a consultant for Steminent Biotherapeutics. They have also received royalty payments as coinventor of varenicline for treating imbalance (patent number 9,463,190) and nonataxic imbalance (patent number 9,782,404). They have also received research/grant support as principal investigator/investigator for studies from AbbVie Inc; Biogen; Biohaven Pharmaceutics; Boston Scientific; Bukwang Pharmaceuticals Co, Ltd; Cala Health, Inc; Cavion; Friedreich’s Ataxia Research Alliance; Houston Methodist Research Institute; National Institutes of Health (READISCA 1.101); Retrotope Inc; and Takeda Inc. SH Kuo is the site primary investigator for the Biohaven SCA and MSA trials and also Sage therapeutic ET trial. They are also the Scientific Advisor for Cadent Therapeutics, Neurocrine, and Praxis. SH Kuo is the Vice Chair for the Movement Disorders Section for American Academy of Neurology and Scientific Program Advisory Committee in American Neurological Association. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.