Dystrophin gene mutations cause dystrophinopathies, a group of phenotypes manifesting with striated muscle involvement. The expression of dystrophin is finely regulated and splicing plays a major role in modulating the phenotype. Recently both in vitro and in vivo modulation of dystrophin mutations by using antisense-mediated targeted exon skipping has been proven to be effective for restoring dystrophin synthesis, opening therapeutic perspectives. There are also increasing evidences that intronic regions contain regulatory elements as well as transcribe for non coding-RNA. The project, taking advantage of a large series of patients with dystrophinopathies available in our Unit, aims at: I) the identification and the characterisation of non–coding RNAs and related regulatory sequences possibly involved in dystrophinopathic phenotypes; ii) the modulation by antisense-mediated targeted exon skipping of dystrophin mutations in patient’s derived myogenic cells. We will search for both conserved and non conserved transcripts within the dystrophin introns. We will investigate both their structural/functional characteristics and their relationship with dystrophin mutations/phenotypes by exploring their transcriptional status in patient’s tissues and by evaluating the occurrence in them of functional motifs. In selected patients with no mutations at the exonic level, we will explore the identified non-coding RNAs for the presence of causative mutations. The identification of as much as possible causative mutations/regulatory motifs in dystrophinopathies is a prerequisite in order to attempt a therapeutic approach for these devastating diseases. Antisense modulation in selected mutations in patient’s derived cells will allow us to restore the wild type RNA phenotype via targeted exon skipping. We will also test in patient’s cells a novel vehicle for antisense oligonucleotide delivery, the core-shell nanospheres, recently proposed as vaccine administration system

Definition of the dystrophin gene transcriptome and modulation of mutations by antisense oligonucleotides-induced targeted exon skipping (Progetto Generale ICE: Industria Chimica Emiliana)

FERLINI, Alessandra
2006

Abstract

Dystrophin gene mutations cause dystrophinopathies, a group of phenotypes manifesting with striated muscle involvement. The expression of dystrophin is finely regulated and splicing plays a major role in modulating the phenotype. Recently both in vitro and in vivo modulation of dystrophin mutations by using antisense-mediated targeted exon skipping has been proven to be effective for restoring dystrophin synthesis, opening therapeutic perspectives. There are also increasing evidences that intronic regions contain regulatory elements as well as transcribe for non coding-RNA. The project, taking advantage of a large series of patients with dystrophinopathies available in our Unit, aims at: I) the identification and the characterisation of non–coding RNAs and related regulatory sequences possibly involved in dystrophinopathic phenotypes; ii) the modulation by antisense-mediated targeted exon skipping of dystrophin mutations in patient’s derived myogenic cells. We will search for both conserved and non conserved transcripts within the dystrophin introns. We will investigate both their structural/functional characteristics and their relationship with dystrophin mutations/phenotypes by exploring their transcriptional status in patient’s tissues and by evaluating the occurrence in them of functional motifs. In selected patients with no mutations at the exonic level, we will explore the identified non-coding RNAs for the presence of causative mutations. The identification of as much as possible causative mutations/regulatory motifs in dystrophinopathies is a prerequisite in order to attempt a therapeutic approach for these devastating diseases. Antisense modulation in selected mutations in patient’s derived cells will allow us to restore the wild type RNA phenotype via targeted exon skipping. We will also test in patient’s cells a novel vehicle for antisense oligonucleotide delivery, the core-shell nanospheres, recently proposed as vaccine administration system
2006
Ferlini, Alessandra
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1679294
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