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Antisense oligonucleotide-induced alternative splicing of the APOB mRNA generates a novel isoform of APOB

Bernard Khoo1, Xavier Roca, Shern L Chew

  • 1Endocrinology, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. b.khoo@qmul.ac.uk

BMC Molecular Biology
|January 20, 2007
PubMed
Abstract

Insights

Antisense oligonucleotides targeting APOB mRNA exon 27 can induce skipping, creating APOB87SKIP27. This approach may lower LDL and cholesterol without affecting APOB48, offering a novel therapeutic strategy.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Apolipoprotein B (APOB) is crucial for lipoprotein particles like LDL and VLDL.
  • APOB has two isoforms: APOB100 (liver) and APOB48 (intestine).
  • Down-regulating APOB100 is a therapeutic target for lowering LDL and cholesterol.

Purpose of the Study:

  • To investigate the efficacy of 2'O-methyl RNA antisense oligonucleotides (ASOs) in inducing APOB mRNA exon 27 skipping.
  • To assess the specificity of ASOs on APOB splicing without affecting other genes.

Main Methods:

  • Utilized 2'O-methyl RNA antisense oligonucleotides (ASOs) targeting splice sites and regulatory elements of APOB exon 27.
  • Tested ASOs in HepG2 cells to evaluate their ability to induce exon skipping.
  • Assessed the impact of ASOs on the splicing of other alternatively spliced genes.

Main Results:

  • ASOs targeting the 5' or 3' splice sites of exon 27, in conjunction with the branch-point sequence, were most effective in inducing exon skipping.
  • The induced exon 27 skipping resulted in the translation of a truncated isoform, APOB87SKIP27.
  • No non-specific effects on the alternative splicing of other genes were observed, indicating targeted action.

Conclusions:

  • Induction of APOB87SKIP27 expression in vivo is predicted to decrease LDL and cholesterol levels, similar to hypobetalipoproteinemia.
  • Exon 27 skipping is unlikely to affect APOB48 expression, as it relies on sequences within exon 26.
  • This exon-skipping strategy presents a potential method for selectively down-regulating APOB100 without impacting intestinal APOB48 production.

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