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Modulating NLRP3 splicing with antisense oligonucleotides to control pathological inflammation.

Roni Klein1,2, Janset Onyuru3, Estela M Viera1,4

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|September 16, 2024
PubMed
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This summary is machine-generated.

Researchers developed splice-switching antisense oligonucleotides (ASOs) to control pathogenic inflammation by targeting the NLRP3 inflammasome. This approach generates non-functional NLRP3 protein variants, effectively reducing inflammation in preclinical models.

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Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Inflammation is crucial for healing but detrimental when unresolved, posing life-threatening risks.
  • The NLRP3 inflammasome, part of the innate immune system, senses cellular stress and is a therapeutic target for inflammatory diseases.
  • Alternative splicing of NLRP3 RNA can produce non-functional protein isoforms, suggesting a regulatory role in inflammasome activation.

Purpose of the Study:

  • To engineer splice-switching antisense oligonucleotides (ASOs) that modulate NLRP3 inflammasome activity.
  • To identify ASOs that induce non-functional NLRP3 spliced isoforms, thereby controlling pathogenic inflammation.
  • To evaluate the efficacy of ASOs in reducing NLRP3 signaling and systemic inflammation.

Main Methods:

  • Screening of antisense oligonucleotides (ASOs) targeting different exons of NLRP3 RNA.
  • Assessing the impact of ASOs on NLRP3 splicing, protein levels, and inflammasome activity in vitro.
  • Testing the most effective ASO in mouse models of acute inflammation and cryopyrin-associated periodic syndrome (CAPS) in vivo.

Main Results:

  • Several ASOs were identified that successfully modulated NLRP3 splicing and reduced inflammasome signaling in vitro.
  • The lead ASO significantly decreased NLRP3 protein levels and inflammasome activation.
  • The most effective ASO demonstrated efficacy in suppressing systemic inflammation in vivo mouse models.

Conclusions:

  • Splice-switching ASOs represent a viable strategy for protein engineering to control protein function.
  • This approach can generate therapeutically relevant NLRP3 isoforms with reduced inflammatory activity.
  • An identified ASO effectively treats pathological inflammation in mice by down-regulating functional NLRP3.