Synthetic molecules to treat Friedreich's ataxia

Synthetic molecules to treat Friedreich's ataxia

Friedreich's ataxia results from mutant expansion of the trinucleotide GAA to DNA sequences that prevent cells from producing enough of a needed protein called frataxin. The lack of frataxin can result in a variety of problems that include loss of muscle control, fatigue, vision or hearing impairment, slurred speech, and serious heart conditions.

Using synthetic RNA or DNA, researchers have identified a way to allow normal frataxin production to resume.

Introducing anti-GAA duplex RNAs or single-stranded locked nucleic acids into patient-derived cells increases FXN protein expression to levels similar to analogous wild-type cells. The data are significant because synthetic nucleic acids that target GAA repeats can be lead compounds for restoring curative FXN levels.

In contrast to the CRISPR genomic editing technique, which requires modifications to genes, the molecules in this study are synthetic. The DNA and RNA belong to classes of molecules that already are being used clinically, making development of a new therapy more straightforward, said Dr. Corey, senior author of the study published in the journal Nature Communications.

For use in Friedreich's ataxia, the remaining challenge will be to adequately deliver the synthetic molecules to tissues that are affected by the disease, but those challenges are being addressed by existing clinical programs targeting Huntington's disease and spinal muscular atrophy, Dr. Corey said.

"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," Dr. Corey said.