Promising Friedreich’s Ataxia Therapy Seen in Synthetic RNA and DNA Agents Used by UT Researchers

Margarida Azevedo, MSc avatar

by Margarida Azevedo, MSc |

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FDA grants orphan drug status to Friedreich's ataxia therapy

University of Texas (UT) Southwestern Medical Center researchers have identified RNA and DNA synthetic agents that increase frataxin levels and alleviate Friedreich’s ataxia (FA), suggesting that synthetic nucleic acids that target the specific disease-causing mutation can be lead compounds for FA therapy. The research paper, “Activating frataxin expression by repeat-targeted nucleic acids,” was published in Nature Communications.

Friedreich’s ataxia is a rare and life-threatening neuromuscular disease characterized by progressive neurodegeneration of nerves and muscles in the nervous system and heart. It is caused by mutations (expansion of the GAA repeat) in the FXN gene that lead to decreased transcription of the gene locus and, consequently, low levels of frataxin (FXN), a protein important for anti-oxidative defense by cells and mitochondrial functioning. Unlike other neurological diseases where a key protein is mutated, in FA the main problem is the low levels of frataxin. As such, therapeutic research has focused on approaches to bring protein expression to normal levels, which would likely slow disease progression.

Among these approaches is the use of agents that reverse post-transcription modifications that contribute to frataxin’s decreased expression. Despite showing promise, these approaches rely on nonspecific gene activation, which can lead to undesired side effects and have slowed the progress of such drugs into clinical use. In contrast, the use of synthetic nucleic acid molecules that complement the mutation might bind the expanded RNA and remove the blocker of transcription. This approach, without the setbacks observed in others, also has the advantage of being a more straightforward possible therapy, as synthetic nucleic acids are already in clinical use.

Dr. David Corey, professor of Pharmacology and Biochemistry, and colleagues developed synthetic RNA and DNA molecules that, when introduced into patient-derived cells, were able to increase frataxin expression to levels similar to those observed in healthy cells. The scientists showed that these molecules were able to prevent the mutant sequence from blocking the FXN gene expression, activating it to produce more protein. Importantly, this approach was selective and did not affect other genes, targeting only the FXN gene.

Dr. Corey said in a news release, “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.”