title: Correction of disease-associated exon skipping by synthetic exon-specific activators.
abstract: Differential exon use is a hallmark of alternative splicing, a prevalent mechanism for generating protein isoform diversity. Many disease-associated mutations also affect pre-mRNA splicing, usually causing inappropriate exon skipping. SR proteins are essential splicing factors that recognize exonic splicing enhancers and drive exon inclusion. To emulate this function of SR proteins, we designed small chimeric effectors comprising a minimal synthetic RS domain covalently linked to an antisense moiety that targets an exon by Watson-Crick base pairing. Here we show that such synthetic effectors can mimic the functions of SR proteins and specifically restore wild type splicing when directed to defective BRCA1 or SMN2 pre-mRNA transcripts. This general approach can be used as a tool to investigate splicing mechanisms and modulate alternative splicing of specific genes, and as a therapeutic strategy to correct splicing defects responsible for numerous diseases.
authors.affiliation: Cold Spring Harbor Laboratory, New York 11724, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Cartegni
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Krainer
mesh_terms: D017398:Alternative Splicing; D017362:Cyclic AMP Response Element-Binding Protein; D005091:Exons; D019398:Genes, BRCA1; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000628:therapy; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D009419:Nerve Tissue Proteins / Q000235:genetics; D017354:Point Mutation; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; D055540:Survival of Motor Neuron 2 Protein
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein