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Therapeutic activity of modified U1 core spliceosomal particles

Author

Listed:
  • Malgorzata Ewa Rogalska

    (Human Molecular Genetics, International Centre for Genetic Engineering and Biotechnology)

  • Mojca Tajnik

    (Human Molecular Genetics, International Centre for Genetic Engineering and Biotechnology)

  • Danilo Licastro

    (CBM S.c.r.l., Area Science Park)

  • Erica Bussani

    (Human Molecular Genetics, International Centre for Genetic Engineering and Biotechnology)

  • Luca Camparini

    (Human Molecular Genetics, International Centre for Genetic Engineering and Biotechnology)

  • Chiara Mattioli

    (Human Molecular Genetics, International Centre for Genetic Engineering and Biotechnology)

  • Franco Pagani

    (Human Molecular Genetics, International Centre for Genetic Engineering and Biotechnology)

Abstract

Modified U1 snRNAs bound to intronic sequences downstream of the 5′ splice site correct exon skipping caused by different types of mutations. Here we evaluate the therapeutic activity and structural requirements of these exon-specific U1 snRNA (ExSpeU1) particles. In a severe spinal muscular atrophy, mouse model, ExSpeU1, introduced by germline transgenesis, increases SMN2 exon 7 inclusion, SMN protein production and extends life span. In vitro, RNA mutant analysis and silencing experiments show that while U1A protein is dispensable, the 70K and stem loop IV elements mediate most of the splicing rescue activity through improvement of exon and intron definition. Our findings indicate that precise engineering of the U1 core spliceosomal RNA particle has therapeutic potential in pathologies associated with exon-skipping mutations.

Suggested Citation

  • Malgorzata Ewa Rogalska & Mojca Tajnik & Danilo Licastro & Erica Bussani & Luca Camparini & Chiara Mattioli & Franco Pagani, 2016. "Therapeutic activity of modified U1 core spliceosomal particles," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11168
    DOI: 10.1038/ncomms11168
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