Friedreich?s ataxia is a debilitating degenerative disease caused by the loss of expression of the frataxin (FXN) gene and subsequent mitochondrial dysfunction in multiple tissues. Patients experience a progressive loss of coordination and cardiomyopathy. The reduced expression of FXN is caused by a GAA trinucleotide repeat expansion in the first intron of the gene. These repeat hyper-expansions present a barrier to transcription elongation by RNA polymerase II (Pol II). At present, there are no effective therapies for Friedreich?s ataxia. Current approaches to treat the disease seek to ameliorate functional defects by boosting mitochondrial function. Additional attempts to develop a therapy by stimulating expression of FXN have yielded mixed results. To overcome these limitations, we created a novel class of synthetic transcription elongation factors (SynTEFs) that specifically target GAA repeat hyper-expansions in FXN and actively enable Pol II transcription elongation across the silenced gene. We have recently demonstrated that SynTEFs can restore FXN expression in unmodified fresh PBMC cells drawn from 11 different patients. Moreover, xenografts bearing the FXN-Luciferase reporter in a human cell line (HEK293) is responsive to subcutaneous delivery of Syn-TEF1. Finally, Syn- TEF1 is able restore mitochondrial function in cells derived from patient cells. Based on these encouraging results, we propose to advance the preclinical development of a therapy for Friedreich?s ataxia. As a first step, the pharmacodynamic and toxicity profiles will be determined. If the molecules meet the key feasibility criteria, we will advance the molecule to the next phase of development. Defining successful treatment regimens through pre-IND studies will be the basis of a phase II SBIR proposal.
Friedreich?s ataxia is a debilitating neurodegenerative disease with no effective treatments. A novel compound that addresses the core etiology of the Friedreich?s ataxia will profoundly improve the lives of patients. Furthermore, a 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.
