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Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells

Andrea E Murmann1, Quan Q Gao2, William E Putzbach2

  • 1Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA a-murmann@northwestern.edu m-peter@northwestern.edu.

EMBO Reports
|February 15, 2018
PubMed

Insights

Trinucleotide repeat (TNR) siRNAs targeting CAG repeats show promise as a novel cancer therapy. These siRNAs induce cancer cell death and slow tumor growth in preclinical models with no observed toxicity.

Area of Science:

  • Genetics
  • Molecular Biology
  • Oncology

Background:

  • Trinucleotide repeat (TNR) expansions, such as the CAG repeat in the huntingtin (HTT) gene causing Huntington's disease (HD), are linked to degenerative disorders.
  • Pathological mechanisms involve RNA and protein from TNR regions, including small interfering RNA (siRNA)-sized fragments.
  • An inverse correlation between HTT repeat length and cancer incidence in HD patients suggests a potential link between TNRs and cancer.

Purpose of the Study:

  • To investigate the potential of TNR-based siRNAs as a novel therapeutic strategy against cancer.
  • To determine the toxicity of CAG TNR-based siRNAs against cancer cells and their efficacy in preclinical cancer models.

Main Methods:

  • Design and synthesis of 60 siRNAs based on various TNRs.
  • Testing the toxicity of TNR-based siRNAs against human and mouse cancer cell lines.
  • Evaluation of siCAG/CUG TNR-based siRNAs in a preclinical mouse model of ovarian cancer.

Main Results:

  • siRNAs based on CAG TNRs demonstrated toxicity towards cancer cells by targeting genes with complementary TNRs.
  • The six members of the CAG/CUG family of TNR-based siRNAs were particularly effective against both human and mouse cancer cells.
  • siCAG/CUG TNR-based siRNAs induced cell death *in vitro* across all tested cancer cell lines and significantly slowed tumor growth in a preclinical ovarian cancer model without causing toxicity in mice.

Conclusions:

  • CAG TNR-based siRNAs represent a novel class of therapeutic agents with potent anticancer activity.
  • These siRNAs selectively target cancer cells, offering a potential new avenue for cancer treatment with minimal side effects.
  • Further exploration of TNR-based siRNAs is warranted for their development as anticancer reagents.
Keywords:
CAG repeatsRNAiTLP nanoparticlescell deathtrinucleotide repeats

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