Molecular Mechanisms and Therapeutics for the GAA·TTC Expansion Disease Friedreich Ataxia

Abstract

Friedreich ataxia (FRDA), the most common inherited ataxia, is caused by transcriptional silencing of the nuclear FXN gene, encoding the essential mitochondrial protein frataxin. Currently, there is no approved therapy for this fatal disorder. Gene silencing in FRDA is due to hyperexpansion of the triplet repeat sequence GAA•TTC in the first intron of the FXN gene, which results in chromatin histone modifications consistent with heterochromatin formation. Frataxin is involved in mitochondrial iron homeostasis and the assembly and transfer of iron-sulfur clusters to various mitochondrial enzymes and components of the electron transport chain. Frataxin insufficiency leads to progressive spinocerebellar neurodegeneration, causing symptoms of gait and limb ataxia, slurred speech, muscle weakness, sensory loss, and cardiomyopathy in many patients, resulting in death in early adulthood. Numerous approaches are being taken to find a treatment for FRDA, including excision or correction of the repeats by genome engineering methods, gene activation with small molecules or artificial transcription factors, delivery of frataxin to affected cells by protein replacement therapy, gene therapy, or small molecules to increase frataxin protein levels, and therapies aimed at countering the cellular consequences of reduced frataxin. This review will summarize the mechanisms involved in repeat-mediated gene silencing and recent efforts aimed at development of therapeutics.

Repeat Expansion Disorders: Mechanisms and Therapeutics

“…Frataxin is a mitochondrial protein and is a component of a multiprotein complex that assembles iron-sulfur clusters. Gottesfeld reviews the molecular mechanisms of FRDA and the numerous interesting approaches to treat the disease [21]. These include excision or correction of the frataxin gene by genome engineering, gene activation with small molecules, protein replacement, and small molecules identified in cellular screens.…”

Neurologic outcomes in Friedreich ataxia

“…Most patients are homozygous for the hyperexpansion of a guanosine-adenosine-adenosine (GAA) repeat in the first intron of the Frataxin (FXN) gene, 1 which triggers the formation of repressive chromatin inhibiting FXN messenger RNA transcription. 2 Longer repeats lead to more severe repression of frataxin expression, such that most residual FXN in patients with FRDA derives from the allele with the shorter GAA repeat (GAA1). Patients with earlier onset and more severe disease usually have longer GAA1.…”

Defining Transcription Regulatory Elements in the Human Frataxin Gene: Implications for Gene Therapy

“…9,10 Although numerous studies point toward transcriptional initiation and/or elongation being affected by the expanded triplets, current knowledge regarding transcription control of the FXN locus in nonmutated alleles is limited. 5,[11][12][13][14][15] All studies reported thus far utilized episomal vectors containing the luciferase gene under the control of putative FXN promoter regions. 10,16 The ''strength'' of the promoter and importance of certain regions were defined relative to the luciferase expression in constructs containing nonmodified fragments of the FXN gene.…”