Delivery of the 135kb human frataxin genomic DNA locus gives rise to different frataxin isoforms

© 2015 Elsevier Inc. Friedreich's ataxia (FRDA) is the most common form of hereditary ataxia caused by recessive mutations in the FXN gene. Recent results have indicated the presence of different frataxin isoforms due to alternative gene expression mechanisms. Our previous studies demonstrated the advantages of using high-capacity herpes simplex virus type 1 (HSV-1) amplicon vectors containing the entire FXN genomic locus (iBAC-FXN) as a gene-delivery vehicle capable of ensuring physiologically-regulated and long-term persistence. Here we describe how expression from the 135. kb human FXN genomic locus produces the three frataxin isoforms both in cultured neuronal cells and also in vivo. Moreover, we also observed the correct expression of these frataxin isoforms in patient-derived cells after delivery of the iBAC-. FXN. These results lend further support to the potential use of HSV-1 vectors containing entire genomic loci whose expression is mediated by complex transcriptional and posttranscriptional mechanisms for gene therapy applications.Spanish National Research Plan (SAF 2012-38042) and the Autonomous Government of Madrid (S2010/BMD-2331). The Center for Biomedical Research on Rare Diseases (“Centro de Investigación Biomédica en Red sobre Enfermedades Raras”, CIBERER) is an initiative supported by the “Instituto de Salud Carlos III”.Peer Reviewe