Pre-clinical development of synthetic transcription elongation factors for the treatment of Friedreich's ataxia

Abstract Friedreich s ataxia is a debilitating degenerative disease caused by the loss of expression of the frataxinFXNgene and subsequent mitochondrial dysfunction in multiple tissuesPatients experience a progressive loss of coordination and cardiomyopathyThe reduced expression of FXN is caused by a GAA trinucleotide repeat expansion in the first intron of the geneThese repeat hyper expansions present a barrier to transcription elongation by RNA polymerase IIPol IIAt presentthere are no effective therapies for Friedreich s ataxiaCurrent approaches to treat the disease seek to ameliorate functional defects by boosting mitochondrial functionAdditional attempts to develop a therapy by stimulating expression of FXN have yielded mixed resultsTo overcome these limitationswe created a novel class of synthetic transcription elongation factorsSynTEFsthat specifically target GAA repeat hyper expansions in FXN and actively enable Pol II transcription elongation across the silenced geneWe have recently demonstrated that SynTEFs can restore FXN expression in unmodified fresh PBMC cells drawn fromdifferent patientsMoreoverxenografts bearing the FXN Luciferase reporter in a human cell lineHEKis responsive to subcutaneous delivery of Syn TEFFinallySynTEFis able restore mitochondrial function in cells derived from patient cellsBased on these encouraging resultswe propose to advance the preclinical development of a therapy for Friedreich s ataxiaAs a first stepthe pharmacodynamic and toxicity profiles will be determinedIf the molecules meet the key feasibility criteriawe will advance the molecule to the next phase of developmentDefining successful treatment regimens through pre IND studies will be the basis of a phase II SBIR proposal Narrative Friedreich s ataxia is a debilitating neurodegenerative disease with no effective treatmentsA novel compound that addresses the core etiology of the Friedreich s ataxia will profoundly improve the lives of patientsFurthermorea new class of SynTEFs has the potential to address other repeat expansion diseases and understanding the response to systemic treatment will lay the foundation for the design of future treatments