Boosting Frataxin expression to treat Friedreich Ataxia

Speaker

• Massimo Pandolfo: Department of Neurology and Neurosurgey - McGill University, Montreal (CA)

Abstract

Friedreich ataxia (FRDA) is the most common form of hereditary ataxia in Europe. It is caused by deficiency of the frataxin protein, leading to impaired mitochondrial biogenesis of Fe/S clusters, loss of activity of multiple Fe/S enzymes, mitochondrial dysfunction, and altered iron metabolism. In most cases, frataxin deficiency is due to impaired transcription of the FXN gene triggered by homozygous intronic expanded GAA repeats via epigenetic changes. Data from cellular and animal models support restoration of frataxin levels as potential therapy for FRDA. 
This can be accomplished in principle by enhancing the transcriptional activity of the endogenous FXN gene or via the introduction of a frataxin-expressing transgene. The use of epigenetic modifiers and AAV-based gene therapy are currently close to or int o clinical testing.
Challenges include targeting all affected cells before they are lost, establish sufficient but not excessive frataxin levels, avoid systemic or local immune reactions, and allow multiple treatments if needed