restoration of full-length smn promoted by adenoviral vectors expressing rna antisense oligonucleotides embedded in u7 snrnas恢复全长smn得到运载体表达反义rna寡核苷酸嵌入得以核内小rna.pdfVIP

Restoration of Full-Length SMN Promoted by Adenoviral Vectors Expressing RNA Antisense Oligonucleotides Embedded in U7 snRNAs Till Geib, Klemens J. Hertel* Department of Microbiology and Molecular Genetics, School of Medicine, University of California Irvine, Irvine, California, United States of America Abstract Background: Spinal Muscular Atrophy (SMA) is an autosomal recessive disease that leads to specific loss of motor neurons. It is caused by deletions or mutations of the survival of motor neuron 1 gene (SMN1). The remaining copy of the gene, SMN2, generates only low levels of the SMN protein due to a mutation in SMN2 exon 7 that leads to exon skipping. Methodology/Principal Findings: To correct SMN2 splicing, we use Adenovirus type 5–derived vectors to express SMN2- antisense U7 snRNA oligonucleotides targeting the SMN intron 7/exon 8 junction. Infection of SMA type I–derived patient fibroblasts with these vectors resulted in increased levels of exon 7 inclusion, upregulating the expression of SMN to similar levels as in non–SMA control cells. Conclusions/Significance: These results show that Adenovirus type 5–derived vectors delivering U7 antisense oligonucleotides can efficiently restore full-length SMN protein and suggest that the viral vector-mediated oligonucleotide application may be a suitable therapeutic approach to counteract SMA. Citation: Geib T, Hertel KJ (2009) Restoration of Full-Length SMN Promoted by Adenoviral Vectors Expressing RNA Antisense Oligonucleotides Embedded in U7 snRNAs. PLoS ONE 4(12): e8204. doi:10.1371/journal.pone.0008204 ´ ` Editor: Juan Valcarcel, Centre de Regulacio Genomica, Spain Received September 13, 2009; Accepted November 11, 2009; Published December 8, 2009 Copyright: 2009 Geib, Hertel. This is an open-access article distributed