OLIGOTHERAPEUTIC STRATEGIES FOR THE TREATMENT OF FRIEDREICHS ATAXIA. F. Ozsolak, D. Jun Li, D. Parekh, D. Knowlton, M. Wysk, R. Subramanian, J. Barsoum RaNA Therapeutics, Cambridge, MA.

   Friedreichs ataxia (FRDA) is a recessively inherited disorder that arises due to cellular depletion of frataxin (FXN) protein and resulting defects in mitochondrial functions. FRDA is a progressive neuromuscular disease which lacks any FDA-approved therapy. The protein coding sequence of FXN is normal in the majority of FRDA patients, and the causative basis of this disease is the under-expression of the FXN gene, suggesting that upregulation of endogenous FXN expression could be an effective therapy. The most common molecular cause of this currently incurable disease is the expansion of GAA/TTC triplet repeats in the first intron of FXN gene. Repeat expansion beyond a certain threshold causes transcriptional defects which reduce FXN mRNA and protein levels. Despite long-standing research in the pathogenesis of FRDA, the means by which GAA-repeat number elevation leads to transcriptional silencing is not clear. Unusual DNA-DNA and DNA-RNA interactions formed in the long triplet repeat stretches, defects and alterations in splicing patterns and the formation of a heterochromatin-like structure are among the hypotheses being considered. In order to gain clues into the mechanisms responsible for the FXN deficit in FRDA, we undertook genome-wide analyses to examine the global and local RNA structure and chromatin structure and composition changes in FRDA patient cells. Epigenetic screens identified two chromatin modifying complexes as being important in establishing and/or maintaining repeat expansion-induced transcriptional repression at the FXN locus. We identified a novel non-coding RNA (ncRNA) potentially responsible for directing the localized epigenetic silencing of the FXN gene. Degrading this ncRNA led to at least partial heterochromatin reversal and FXN mRNA and protein level upregulation to therapeutically significant levels. The oligonucleotide-based therapeutic approaches developed here pave the way towards the design of multiple strategies for the treatment of FRDA and may have applications for the treatment of other human diseases. You may contact the first author (during and after the meeting) at fozsolak@ranarx.com.

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