title: Delivery of the 135 kb human frataxin genomic DNA locus gives rise to different frataxin isoforms.
abstract: 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.
authors.affiliation: Departamento Biología Molecular and Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), Universidad Autónoma de Madrid, 28049 Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Spain; Instituto de Investigación Sanitaria Puerta de Hierro-Majadahonda, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Pérez-Luz
authors.affiliation: Karolinska Institute, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Gimenez-Cassina
authors.affiliation: Departamento Biología Molecular and Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), Universidad Autónoma de Madrid, 28049 Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Spain; Instituto de Investigación Sanitaria Puerta de Hierro-Majadahonda, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Fernández-Frías
authors.affiliation: Oxford University, Oxford, United Kingdom.
authors.forename: R
authors.initials: R
authors.lastname: Wade-Martins
authors.affiliation: Departamento Biología Molecular and Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), Universidad Autónoma de Madrid, 28049 Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Spain; Instituto de Investigación Sanitaria Puerta de Hierro-Majadahonda, Spain. Electronic address: javier.diaznido@uam.es.
authors.forename: J
authors.initials: J
authors.lastname: Díaz-Nido
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D022202:Chromosomes, Artificial, Bacterial; D005621:Friedreich Ataxia / Q000235:genetics*; D056426:Genetic Loci; D005822:Genetic Vectors; D015894:Genome, Human; D018259:Herpesvirus 1, Human / Q000235:genetics; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D000096923:Frataxin
chemical_list: D033862:Iron-Binding Proteins; D020033:Protein Isoforms; D000096923:Frataxin
keywords: Bacterial artificial chromosomes; Frataxin; Friedreich's ataxia; Gene therapy; HSV-1 amplicons