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Genome and transcriptome analysis to identify splicing defects and in vivo evaluation of antisense therapy

17th national competition for scientific and technical research

Rare diseases

Senior Researcher : Lourdes Ruiz Desviat

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Research Centre or Institution : Centro de Biología Molecular "Severo Ochoa". CSIC-Universidad Autónoma de Madrid


Approximately a third of mutations which cause disease affect the splicing process, which is normally located at exon-intron connections, but they can also occur in other internal intronic sequences, such as those which activate the insertion of pseudoexons. Massive sequencing is changing the genetic diagnosis panorama, as it makes it fast and economical to analyse complete intronic sequences, as well as to analyse the transcriptome to identify aberrant transcripts. This project aims to apply the aforesaid techniques to complete analysis of the genome of patients with hereditary metabolic diseases (HMD) with an incomplete genotype, together with transcriptome analysis in selected cellular lines, with the aim of identifying pseudoexons and pathological intronic mutations that affect the splicing process. This will be confirmed by functional analysis using minigenes. Meanwhile, splicing defects are the object of targeted therapies, some of which are now in clinical phase, such as the use of antisense oligonucleotides (AON) which block access by the splicing machinery to selected regions, forcing the exclusion of exons or pseudoexons, or preventing the use of cryptic locations. Very recently it has been suggested that the strategies for administering AON in vivo should include the use of plasmid vectors without bacterial sequences (minicircles) which are carriers of snRNAU7-AON fusions that give rise to long-lasting effect of the biological action of AON. This project will investigate the therapeutic potential in murine models of U7-AON micro-minicircles to check the in vivo efficacy of antisense therapy in HMD.

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