Friedreich’s ataxia is a progressive, autosomal recessive ataxia caused, in most cases, by homozygous expansion of GAA•TTC triplet-repeats in the first intron of the frataxin gene. GAA•TTC repeat expansion results in the formation of a non-B DNA intramolecular triplex as well as changes in the epigenetic landscape at the frataxin locus. Expansion of intronic GAA•TTC repeats is associated with reduced levels of frataxin mRNA and protein, resulting in disease development. In our previous study, we demonstrated that DNA-binding anti-gene oligonucleotides specifically targeting the GAA•TTC repeat expansion effectively disrupted the formation of intramolecular triplex structures. In this study, we extend these findings by showing that targeting repeat-expanded chromosomal DNA with anti-gene oligonucleotides leads to an increase in frataxin mRNA and protein levels in cells derived from Friedreich’s ataxia patients. We examined numerous anti-gene oligonucleotides and found that the design, length, and their locked nucleic acid composition have a high impact on the effectiveness of the treatment. Collectively, our results demonstrate the unique capability of specifically designed oligonucleotides targeting the GAA•TTC DNA repeats to upregulate frataxin gene expression.
Monday, May 5, 2025
Anti-gene oligonucleotides targeting Friedreich’s ataxia expanded GAA•TTC repeats increase Frataxin expression
Negin Mozafari, Salomé Milagres, Tea Umek, Cristina S.J. Rocha, Claudia Marina Vargiu, Fiona Freyberger, Osama Saher, Marek Napierala, Jill S. Napierala, Pontus Blomberg, Per T. Jørgensen, Tanel Punga, C. I. Edvard Smith, Jesper Wengel, Rula Zain, Anti-gene oligonucleotides targeting Friedreich’s ataxia expanded GAA•TTC repeats increase Frataxin expression, Molecular Therapy Nucleic Acids, 2025, 102541, doi:10.1016/j.omtn.2025.102541.
