Alleviating transcript insufficiency caused by Friedreich's ataxia triplet repeats

Expanded GAA.TTC trinucleotide repeats in intron 1 of the frataxin gene cause Friedreich's ataxia (FRDA) by reducing frataxin mRNA levels. Insufficient frataxin, a nuclear encoded mitochondrial protein, leads to the progressive neurodegeneration and cardiomyopathy characteristic of FRDA, Previously we demonstrated that long GAA.TTC tracts impede transcription elongation in vitro and provided evidence that the impediment results from an intramolecular purine.purine.pyrimidine DNA tripler formed behind an advancing RNA polymerase, Our model predicts that inhibiting formation of this tripler during transcription will increase successful elongation through GAA.TTC tracts, Here we show that this is the case, Oligodeoxyribonucleotides designed to block particular types of tripler formation provide specific and concentration-dependent increases in full-length transcript, In principle, therapeutic agents that selectively interfere with tripler formation could alleviate the frataxin transcript insufficiency caused by pathogenic FRDA alleles.