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Spinal muscular atrophy: SMN2 pre-mRNA splicing corrected by a U7 snRNA derivative carrying a splicing enhancer sequence.
- Source :
-
Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2007 Aug; Vol. 15 (8), pp. 1479-86. Date of Electronic Publication: 2007 Jun 05. - Publication Year :
- 2007
-
Abstract
- Spinal muscular atrophy (SMA) is a lethal hereditary disease caused by homozygous deletion/inactivation of the survival of motoneuron 1 (SMN1) gene. The nearby SMN2 gene, despite its identical coding capacity, is only an incomplete substitute, because a single nucleotide difference impairs the inclusion of its seventh exon in the messenger RNA (mRNA). This splicing defect can be corrected (transiently) by specially designed oligonucleotides. Here we have developed a more permanent correction strategy based on bifunctional U7 small nuclear RNAs (snRNAs). These carry both an antisense sequence that allows specific binding to exon 7 and a splicing enhancer sequence that will improve the recognition of the targeted exon. When expression cassettes for these RNAs are stably introduced into cells, the U7 snRNAs become incorporated into small nuclear ribonucleoprotein (snRNP) particles that will induce a durable splicing correction. We have optimized this strategy to the point that virtually all SMN2 pre-mRNA becomes correctly spliced. In fibroblasts from an SMA patient, this approach induces a prolonged restoration of SMN protein and ensures its correct localization to discrete nuclear foci (gems).
- Subjects :
- Base Sequence
Cell Line
Cyclic AMP Response Element-Binding Protein genetics
DNA, Antisense genetics
Exons genetics
Fibroblasts
Humans
Molecular Sequence Data
Muscular Atrophy, Spinal pathology
Nerve Tissue Proteins genetics
RNA, Messenger genetics
RNA-Binding Proteins genetics
SMN Complex Proteins
Survival of Motor Neuron 1 Protein
Survival of Motor Neuron 2 Protein
Time Factors
Cyclic AMP Response Element-Binding Protein metabolism
Muscular Atrophy, Spinal genetics
Muscular Atrophy, Spinal metabolism
Nerve Tissue Proteins metabolism
RNA Splicing genetics
RNA, Small Nuclear genetics
RNA-Binding Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1525-0016
- Volume :
- 15
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 17505471
- Full Text :
- https://doi.org/10.1038/sj.mt.6300200