Journal of Inherited Metabolic Disease

, Volume 33, Issue 4, pp 397–403

Present and future of antisense therapy for splicing modulation in inherited metabolic disease

  • Belen Pérez
  • Laura Rodríguez-Pascau
  • Luisa Vilageliu
  • Daniel Grinberg
  • Magdalena Ugarte
  • Lourdes R. Desviat


The number of mutations identified deep in introns which activate or create novel splice sites resulting in pathogenic pseudoexon inclusion in mRNA continues to grow for inherited metabolic disease (IMD) and other human genetic diseases. A common characteristic is that the native splice sites remain intact thus retaining the potential for normal splicing. Antisense oligonucleotides (AO) have been shown to modulate the splicing pattern by steric hindrance of the recognition and binding of the splicing apparatus to the selected sequences. In the case of pseudoexons, AO force the use of the natural splice sites, recovering normally spliced transcripts encoding functional protein. This review summarizes the present knowledge of antisense splicing modulation as a molecular therapy approach for pseudoexon-activating mutations, with a focus in IMD. Although the feasibility of treatment for patients with IMD has yet to be proven, it appears to be clinically promising, as positive results have been reported in cellular and animal models of disease, and antisense therapy for splicing modulation is currently in the clinical trials phase for Duchenne muscular dystrophy patients. Here, we review the most recent advances in AO stability, targeting and delivery, and other issues to be considered for an effective treatment in the clinical setting. Although the number of patients who can be potentially treated is low for each IMD, it represents an excellent therapeutical option as a type of personalized molecular medicine which is especially relevant for diseases for which there is, to date, no efficient treatment.


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Copyright information

© SSIEM and Springer 2010

Authors and Affiliations

  • Belen Pérez
    • 1
    • 2
  • Laura Rodríguez-Pascau
    • 3
    • 4
  • Luisa Vilageliu
    • 3
    • 4
  • Daniel Grinberg
    • 3
    • 4
  • Magdalena Ugarte
    • 1
    • 2
  • Lourdes R. Desviat
    • 1
    • 2
  1. 1.Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular Severo Ochoa, UAM-CSICUniversidad Autónoma de MadridMadridSpain
  2. 2.Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)MadridSpain
  3. 3.Departament de Genetica, Institut de Biomedicina de la Universitat de Barcelona (IBUB)Universitat de BarcelonaBarcelonaSpain
  4. 4.Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)BarcelonaSpain

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