Synthetic Nucleic Acids Restore Normal Frataxin Levels in Patient-Derived Friedreich's Ataxia Cells

Neurological disease researchers have used synthetic nucleic acid polymers to block the defective FXN gene segment and restore normal levels of frataxin in cells derived from patients with Freidreich's ataxia.

Friedreich's ataxia is an autosomal recessive disorder that occurs when the FXN gene contains amplified repeats of the GAA (guanine-adenine-adenine) nucleotide sequence. The FXN gene encodes the protein frataxin, but GAA repeat expansion causes frataxin levels to be reduced. Frataxin is an iron-binding protein responsible for forming iron-sulfur clusters. One result of frataxin deficiency is mitochondrial iron overload which can cause damage to many proteins, which can result in a variety of symptoms that include loss of muscle control, fatigue, vision or hearing impairment, slurred speech, and serious heart conditions.


Investigators at the University of Texas Southwestern Medical Center (Dallas, USA) developed synthetic nucleic acids to block the effects of GAA expansion and restore normal frataxin levels.

In a paper published in the February 4, 2016, online edition of the journal Nature Communications the investigators reported that by introducing anti-GAA duplex RNAs or single-stranded locked nucleic acids into patient-derived cells, they were able to increase frataxin expression to levels similar to analogous wild-type cells. These results were considered to be significant, since synthetic nucleic acids that target GAA repeats could lead to the development of compounds for restoring curative frataxin levels. More broadly, they demonstrated a new strategy for upregulating gene expression.

"The problem arises because of a mutation within the frataxin gene (FXN) that does not code for protein. In this case, the mutation causes the synthesis of a longer piece of RNA. This longer sequence binds the DNA and gums up the works, blocking RNA production needed to produce the frataxin protein," said senior author Dr. David Corey, professor of pharmacology and biochemistry at the University of Texas Southwestern Medical Center. "The synthetic DNA or RNA prevents the mutant sequence from bending back and blocking the frataxin gene. This action activates the frataxin gene, which then makes frataxin RNA and protein at normal levels. In addition, our approach is selective for targeting the frataxin gene FXN and does not affect other genes."

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University of Texas Southwestern Medical Center