None approved for ASO; Omaveloxolone (Skyclarys) approved for Friedreich ataxia but is not an ASO
Friedreich ataxia (FA) is the most common inherited ataxia, affecting approximately 1 in 50,000 people. It is an autosomal recessive disorder caused by a GAA trinucleotide repeat expansion in intron 1 of the FXN gene, which encodes frataxin — a mitochondrial protein essential for iron-sulfur cluster assembly and iron homeostasis. Normal individuals have 5–33 GAA repeats; affected individuals typically have 66 to more than 1,000 repeats on both alleles.
The disease typically presents in adolescence with progressive gait and limb ataxia (loss of coordination), dysarthria (speech difficulties), loss of deep tendon reflexes, and sensory neuropathy. Most patients develop hypertrophic cardiomyopathy, the leading cause of death. Scoliosis and diabetes mellitus are common. Most patients require a wheelchair within 10–15 years of onset, and life expectancy is reduced to 40–50 years.
The expanded GAA repeat in FXN does not produce a toxic protein (unlike Huntington’s disease). Instead, the repeat expansion causes the DNA to adopt abnormal structures (R-loops and sticky DNA) and triggers epigenetic silencing of the FXN gene through heterochromatin formation. The result is severe reduction in frataxin protein production — patients typically produce only 5–30% of normal frataxin levels. Importantly, the FXN coding sequence is intact; the gene is simply silenced by the expanded repeat.
This makes Friedreich ataxia amenable to ASO strategies that reactivate or upregulate FXN expression. ASOs can be designed to target the expanded GAA repeat region, disrupting the R-loop structures or heterochromatin formation that silence the gene. By relieving this epigenetic silencing, the cell can resume producing frataxin from the intact coding sequence. Preclinical studies have shown that ASOs targeting the GAA repeat or associated regulatory elements can increase frataxin mRNA and protein levels.
Omaveloxolone (Skyclarys), approved in 2023, is the first FDA-approved treatment for Friedreich ataxia, but it is a small-molecule Nrf2 activator that addresses downstream oxidative stress — it is not an ASO and does not directly increase frataxin levels. ASO approaches aim to address the root cause by restoring frataxin production.
Pequliar designs ASO candidates for Friedreich ataxia that target the FXN gene with the goal of increasing frataxin expression. The platform identifies optimal binding sites, scores candidates for thermodynamic properties and off-target safety, and provides synthesis-ready sequences with full chemistry assignment for research and preclinical evaluation.
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Start a designPequliar is a computational research tool for informational purposes only. All sequences are computationally predicted candidates that have not been experimentally validated. Pequliar does not prescribe, recommend, or administer any compound. Independent validation by qualified professionals is required.