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Antisense oligonucleotides against Il6ra ameliorate cancer cachexia in mice

Yuanyuan Wang1, Qingtao Sun1, Wenqiang Zheng1

  • 1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|August 20, 2026
PubMed

Insights

A new antisense oligonucleotide (ASO) therapy targets brain interleukin-6 receptor (IL-6R) to treat cancer cachexia. This approach reduces IL-6R in the brainstem, alleviating cachectic symptoms and potentially extending survival in mouse models.

Area of Science:

  • Neuroscience
  • Oncology
  • Pharmacology

Background:

  • Interleukin-6 (IL-6) is crucial in developing cancer cachexia.
  • IL-6 signals through neurons in the brainstem's area postrema to drive cachexia.
  • No approved treatments currently exist for cancer cachexia.

Purpose of the Study:

  • To develop a novel splice-switching antisense oligonucleotide (ASO)-based therapy targeting IL-6 receptor (IL-6R) expression in the brain.
  • To evaluate the efficacy of ASO treatment in mouse models of cancer cachexia.

Main Methods:

  • Developed splice-switching antisense oligonucleotides (ASOs) to reduce IL-6R expression.
  • Administered a single dose of ASOs via intracerebroventricular injection in mouse models.
  • Analyzed IL-6R levels, cachectic symptoms, survival rates, and transcriptomic changes.

Main Results:

  • ASO treatment reduced IL-6R levels in the brainstem and ameliorated cachectic symptoms in mouse models.
  • Survival was extended in one of the cancer cachexia models.
  • ASO treatment decreased cancer-associated inflammatory pathway activation in the brainstem and skeletal muscle.

Conclusions:

  • Splice-switching ASO therapy targeting brain IL-6R offers a promising new approach for treating cancer cachexia.
  • Developed ASOs capable of suppressing human IL-6R, supporting potential clinical translation.
  • This study provides a novel therapeutic strategy for managing cancer cachexia.

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