Therapeutic approaches for the treatment of Friedreich’s ataxia

Abstract

Friedreich ataxia (FRDA) is an inherited, progressive, neurodegenerative disease for which there is presently no cure or effective therapeutic intervention. While physiologically complex, FRDA is caused by deficits in production and expression of frataxin (FXN), a mitochondrial protein important for regulation of iron-sulfur cluster containing enzymes in the cell. Depletion of FXN is associated with dysfunction of ATP synthesis, mitochondrial iron accumulation, potentially an increase in oxidative stress, and cellular dysfunction. Therapeutic development presently focuses on improving mitochondrial function and increasing FXN expression. Gene therapy, a field which has undergone significant advances in recent years, may offer a promising treatment for FRDA in the future. This collection of approaches provides many possible opportunities for treating this multisystem disorder.

Keywords::

• coenzyme Q10
• deferiprone
• EPI-743
• EPO
• Friedreich ataxia
• gene therapy
• idebenone
• mitochondrial dysfunction
• tat-frataxin

Financial & competing interests disclosure

D Lynch has received grant funding on Friedreich’s ataxia from the Friedreich’s ataxia research Allaince, MDA, Santhera, Penwest, Edison, Viropharma/Shire. He has performed consulting work for Retrotope and Apopharma and has collaborated scientifically with Repligen. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Currently, no therapeutic approach has been proven effective in treating Friedreich’s ataxia or slowing its progression; however, numerous drugs are in various phases of development and testing.

• Therapeutic development for treating Friedreich’s ataxia falls into two main categories: therapies related to mitochondrial functioning and those that increase frataxin expression. An alternative to drug-based treatment is gene therapy.

• Therapies related to mitochondrial functioning include idebenone, coenzyme Q10, EPI-743, VP-20629, deferiprone, PGC-1α and deuterated fatty acids.

• Therapies to increase frataxin include erythropoitin, TAT frataxin, interferon γ, histone deacetylase inhibition and nicotinamide.

• Gene therapy: Animal studies have been encouraging by preventing and even reversing histological and functional features of cardiomyopathy in Friedreich’s ataxia mouse models. While promising, potential safety and logistic concerns require an appropriately vigilant approach.

Notes