DNA-like Compounds May Lead to New Way of Treating Friedreich’s Ataxia

DNA-like compounds that appear to correct the abnormal three-dimensional structures formed in the mutated region of the frataxin gene — the culprit of Friedreich’s ataxia — may open research into how the atypical structures prevent the gene from working. This, in turn, could lead to the development of drugs that restore normal levels of frataxin protein production in patients with the disease.

The study detailing this process, “Disruption of Higher Order DNA Structures in Friedreich’s Ataxia (GAA)n Repeats by PNA or LNA Targeting,” was recently published in the journal PLOS ONE.

The GAA repeats present in the frataxin gene prevent the production of the protein by folding in abnormal ways. The structure includes the formation of triple coils, instead of the usual double-stranded DNA molecules. Single-stranded DNA stretches can also be present.

These abnormal structures prevent the machinery that produces proteins from the gene blueprint from doing its work.

Oligonucleotides, the compounds used in the study, are made of the same type of material as DNA. They have the capacity to bind to DNA and impact the way the gene folds.

Researchers at the two Swedish institutions, Uppsala University and Karolinska Institutet, tested peptide nucleic acid (PNA) and locked nucleic acid (LNA) — two such DNA-like compounds — for their ability to prevent the abnormal folding of the frataxin gene.

The team inserted DNA stretches, holding various numbers of GAA repeats, into a part of DNA derived from the frataxin gene. In this way, they created a short version of the DNA stretch with nine repeats, a medium version with 75 repeats, and a long version holding 115 GAA repeats.

They discovered that the inserted repeats formed triple-stranded molecules, independent of the number of GAA repeats. Single-stranded DNA was only found in DNA constructs with short and long GAA repeats.

Testing the PNA compound holding four GAA repeats entirely prevented the formation of triple-stranded DNA molecules. Using PNA with repeats of the DNA bases CTT, in contrast, promoted the formation of triple-stranded structures.

LNA compounds also worked to prevent the formation of triple structures. This allowed the DNA molecule to take on a more relaxed three-dimensional fold, better resembling the normal folding seen in double-stranded DNA molecules.