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Redirecting splicing with bifunctional oligonucleotides.

Jean-Philippe Brosseau1, Jean-François Lucier, Andrée-Anne Lamarche

  • 1Laboratory of Functional Genomics and Research Centre on RNA Biology of the Université de Sherbrooke, Sherbrooke, Quebec J1E 4K8, Canada, Department of Biochemistry, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec J1E 4K8, Canada and Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec J1E 4K8, Canada.

Nucleic Acids Research
|December 31, 2013
PubMed
Summary
This summary is machine-generated.

Bifunctional oligonucleotides, including targeted oligonucleotide silencers (TOSS) and enhancers (TOES) of splicing, offer a versatile approach to modulate alternative splicing. This study demonstrates their broad applicability and develops a predictive algorithm for TOSS design.

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Area of Science:

  • Molecular Biology
  • Genetics
  • RNA Biology

Background:

  • Alternative splicing generates diverse protein isoforms, crucial for cellular function.
  • Dysregulation of alternative splicing contributes to various human diseases.
  • Bifunctional oligonucleotides (TOSS and TOES) can modulate splicing but have limited applications.

Purpose of the Study:

  • To expand the utility of TOSS and TOES for modulating alternative splicing.
  • To develop a predictive algorithm for designing effective TOSS.
  • To demonstrate the potential of bifunctional oligonucleotides in therapeutic strategies for splicing-related disorders.

Main Methods:

  • Tested TOSS on over 50 alternative splicing events across various genes.
  • Developed and validated an algorithm for TOSS design.
  • Engineered a TOES to recruit TDP-43 to enhance exon inclusion, demonstrated in the SMN2 gene.

Main Results:

  • Demonstrated the broad applicability and robustness of TOSS across diverse splicing events.
  • Achieved an 80% success rate in designing active TOSS using the developed algorithm.
  • Successfully enhanced exon inclusion using a TDP-43-recruiting TOES in the SMN2 gene.

Conclusions:

  • Bifunctional oligonucleotides are effective tools for redirecting alternative splicing.
  • The developed algorithm significantly improves TOSS design efficiency.
  • These findings support the use of bifunctional oligonucleotides as a promising strategy for therapeutic manipulation of splice variants.