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Projects. Life and Matter Sciences

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

Lead Researcher:
Lourdes Ruiz Desviat

Research Centre:
Centro de Biología Molecular Severo Ochoa. CSIC-UAM.


Lourdes Ruiz DesviatApproximately 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.

Researcher's website:

Lourdes Ruiz Desviat

Doctor in Biology, Universidad Autónoma de Madrid, 1990. Tenured Professor of the Department of Molecular Biology of the UAM and Head of the line of research into the "molecular bases of hereditary metabolic diseases and research into new therapies" in the Centro de Biología Molecular Severo Ochoa. Member of the CIBER de Enfermedades Raras (CIBERER) and the Instituto de Investigación Sanitaria IdiPaz. She is head of genetic diagnostics in the Centro de Diagnóstico de Enfermedades Moleculares (CEDEM).

Her research work covers the study of the molecular bases of phenylketonuria and other organic acidemias, together with the development of new therapeutic strategies. Among others, her most outstanding achievements include the elucidation of the molecular mechanism underlying the response to treatment with cofactor BH4 in phenylketonuria, and the application of antisense therapy to correct splicing mutations in neurometabolic diseases. She has established the testing of the concept of the therapeutic use of end suppressor compounds in organic acidurias. Likewise, she is characterising mitochondrial dysfunction and the implication of miRNA in the pathology of propionic acidemia.

She has been the head researcher in competitive national projects since 2001. Her scientific production includes 110 publications in indexed journals, some with a high impact index in the area of Genetics, and more than 200 communications to congresses.

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