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In Vivo Administration of Therapeutic Antisense Oligonucleotides

Luisa Statello1, Mohamad Moustafa Ali1, Chandrasekhar Kanduri2

  • 1Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Methods in Molecular Biology (Clifton, N.J.)
|December 16, 2020
PubMed

Insights

New locked nucleic acid antisense oligonucleotide (LNA-ASO) delivery methods show promise for cancer therapy by effectively reducing tumor growth. These advanced therapies target long noncoding RNAs (lncRNAs) and overcome previous limitations of toxicity and stability.

Area of Science:

  • Genomics and Molecular Biology
  • Cancer Research
  • RNA Therapeutics

Background:

  • Mammalian genomes express numerous long noncoding RNAs (lncRNAs).
  • A significant portion of lncRNAs are implicated in cancer development and progression.
  • Antisense oligonucleotide (ASO) therapies targeting lncRNAs offer therapeutic potential for cancers.

Purpose of the Study:

  • To evaluate novel locked nucleic acid antisense oligonucleotide (LNA-ASO) delivery strategies for cancer treatment.
  • To address limitations of existing ASO therapies, including cellular toxicity and poor stability/uptake.
  • To assess the efficacy and safety of LNA-ASO delivery in preclinical cancer models.

Main Methods:

  • Development and application of two distinct LNA-ASO delivery approaches: peritumoral administration and systemic delivery.
  • Utilized xenograft models of lung adenocarcinoma to test therapeutic efficacy.
  • Monitored tumor growth and assessed cellular toxicity in response to LNA-ASO treatment.

Main Results:

  • Both peritumoral and systemic LNA-ASO delivery significantly reduced tumor growth in lung adenocarcinoma xenograft models.
  • The LNA-ASO delivery approaches demonstrated a lack of induced toxicity.
  • Improvements in stability and tissue uptake were achieved through LNA technology.

Conclusions:

  • Locked nucleic acid (LNA) technology represents a significant advancement in antisense oligonucleotide (ASO) chemistry for cancer therapy.
  • Novel LNA-ASO delivery methods, including peritumoral and systemic administration, are effective in reducing tumor progression.
  • These findings suggest that LNA-ASO therapies hold considerable potential for treating cancers with improved safety and efficacy profiles.
Keywords:
Antisense oligonucleotidesLNA-ASOsLong noncoding RNAsLung cancerXenograftslncRNAs

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