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Publication Detail
Exon Skipping of Hepatic APOB pre-mRNA with Splice-switching Oligonucleotides Reduces LDL Cholesterol In Vivo
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Disterer P, Al-Shawi R, Ellmerich S, Waddington SN, Owen JS, Simons JP, Khoo B
  • Publication date:
    15/01/2013
  • Journal:
    Molecular Therapy
  • Status:
    Published
  • Country:
    UK
  • Language:
    English
  • Keywords:
    Apolipoprotein B, Exon Skipping, Familial hypercholesterolaemia, Oligoribonucleotides, Quantitative reverse-transcription polymerase chain reaction, Splice-switching oligonucleotides
  • Addresses:
    Petra Disterer
    UCL Medical School
    Institute for Liver and Digestive Health
    Rowland Hill Street
    London
    NW3 2PF
    UK

    Raya Al-Shawi
    Centre for Biomedical Science
    UCL Medical School
    Rowland Hill Street
    London
    NW3 2PF
    UK

    Stephan Ellmerich
    UCL Medical SChool
    Centre for Amyloidosis and Acute Phase Proteins
    Rowland Hill St
    London
    NW3 2PF
    UK

    Simon Waddington
    UCL Medical School
    Institute for Women's Health
    74 Huntley Street
    London
    WC1E 6AU
    UK

    James Owen
    UCL Medical School
    Institute for Liver and Digestive Health
    Rowland Hill St
    London
    NW3 2PF
    UK

    J Paul Simons
    UCL Medical School
    Centre for Amyloidosis and Acute Phase Proteins
    Rowland Hill St
    London
    NW3 2PF
    UK

    Bernard Khoo
    UCL Medical School
    Endocrinology
    Rowland Hill St
    London
    NW3 2PF
    UK
Abstract
Familial hypercholesterolemia (FH) is a genetic disorder characterized by extremely high levels of plasma low-density lipoprotein (LDL), due to defective LDL receptor-Apolipoprotein B (APOB) binding. Current therapies such as statins or LDL apheresis for homozygous FH are insufficiently efficacious at lowering LDL cholesterol or are expensive. Treatments that target APOB100, the structural protein of LDL particles, are potential therapies for FH. We have developed a series of APOB-directed splice-switching oligonucleotides (SSOs) that cause the expression of APOB87, a truncated isoform of APOB100. APOB87, like similarly truncated isoforms expressed in patients with a different condition, familial hypobetalipoproteinemia, lowers LDL cholesterol by inhibiting VLDL assembly and increasing LDL clearance. We demonstrate that these “APO-skip” SSOs induce high levels of exon skipping and expression of the APOB87 isoform, but do not substantially inhibit APOB48 expression in cell lines. A single injection of an optimized APO-skip SSO into mice transgenic for human APOB resulted in abundant exon skipping that persists for more than 6 d. Weekly treatments generated a sustained reduction in LDL cholesterol levels of 34-51% in these mice, superior to Pravastatin in a head-to-head comparison. These results validate APO-skip SSOs as a candidate therapy for FH.
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