repeat GAA results in Friedreich's ataxia. This expanded repeat causes R-loop formation, and using a repeat-targeted oligonucleotide to disrupt the R-loop can reactivate frataxin expression. 96% of FRDA patients have a GAA trinucleotide repeat expansion in intron 1 of both alleles of their FXN gene. Overall, this leads to a decrease in frataxin mRNA synthesis and a decrease (but not absence) in frataxin protein in people with FRDA. (A subset of FRDA patients have GAA expansion in one chromosome and a point mutation in the FXN exon in the other chromosome.) In the typical case, the length of the allele with the shorter GAA expansion inversely correlates with frataxin levels. FRDA patients’ peripheral tissues typically have less than 10% of the frataxin levels exhibited by unaffected people. Lower levels of frataxin result in earlier disease onset and faster progression. FRDA is characterized by ataxia, sensory loss, and cardiomyopathy. The reason frataxin deficiency causes these symptoms is not entirely clear. On a cellular level, it is linked to iron accumulation in the mitochondria and increased oxidant sensitivity. For reasons that are not well understood, this primarily affects the tissue of the dorsal root ganglia, cerebellum, and heart muscle. Animal studies In mice, complete inactivation of the FXN gene is lethal in the early embryonic stage. Although nearly all organisms express a frataxin homologue, the GAA repeat in intron 1 only exists in humans and other primates, so the mutation that causes FDRA can't occur naturally in other animals. Scientists have developed several options to model this disease in mice. One approach is to silence frataxin expression in just one specific tissue type of interest: the heart (mice modified this way are called MCK), all neurons (NSE), or just the spinal cord and cerebellum (PRP). Another approach involves inserting a GAA expansion into the first intron of the mouse FXN gene, which should inhibit frataxin production, just like in humans. Mice that are homozygous for this modified gene are called KIKI (knock-in knock-in), and the compound heterozygotes formed by crossing KIKI mice with frataxin knockout mice are called KIKO (knock-in knock-out). However, even KIKO mice still express 25-36% of the normal frataxin level, and show very mild symptoms. The final approach involves creating transgenic mice with a GAA-expanded version of the human frataxin gene. These mice are called YG22R (one GAA sequence of 190 repeats) and YG22R (two GAA sequences of 90