Quantifying the activity profile of ASO and siRNA conjugates in glioblastoma xenograft tumors in vivo.

in Nucleic acids research by Samantha L Sarli, Hassan H Fakih, Karen Kelly, Gitali Devi, Julia M Rembetsy-Brown, Holly R McEachern, Chantal M Ferguson, Dimas Echeverria, Jonathan Lee, Jacquelyn Sousa, Hanadi F Sleiman, Anastasia Khvorova, Jonathan K Watts

TLDR

  • The study looked at how different types of chemicals called oligonucleotides can be used to treat a type of brain tumor called glioblastoma. The researchers found that some types of oligonucleotides work better in the brain than others, and that adding certain chemicals called lipids to the oligonucleotides can make them work even better. The study also found that some types of lipids can be harmful to the brain, so the researchers need to find the right balance between effectiveness and safety.

Abstract

Glioblastoma multiforme is a universally lethal brain tumor that largely resists current surgical and drug interventions. Despite important advancements in understanding GBM biology, the invasiveness and heterogeneity of these tumors has made it challenging to develop effective therapies. Therapeutic oligonucleotides-antisense oligonucleotides and small-interfering RNAs-are chemically modified nucleic acids that can silence gene expression in the brain. However, activity of these oligonucleotides in brain tumors remains inadequately characterized. In this study, we developed a quantitative method to differentiate oligonucleotide-induced gene silencing in orthotopic GBM xenografts from gene silencing in normal brain tissue, and used this method to test the differential silencing activity of a chemically diverse panel of oligonucleotides. We show that oligonucleotides chemically optimized for pharmacological activity in normal brain tissue do not show consistent activity in GBM xenografts. We then survey multiple advanced oligonucleotide chemistries for their activity in GBM xenografts. Attaching lipid conjugates to oligonucleotides improves silencing in GBM cells across several different lipid classes. Highly hydrophobic lipid conjugates cholesterol and docosanoic acid enhance silencing but at the cost of higher neurotoxicity. Moderately hydrophobic, unsaturated fatty acid and amphiphilic lipid conjugates still improve activity without compromising safety. These oligonucleotide conjugates show promise for treating glioblastoma.

Overview

  • The study aims to investigate the differential silencing activity of oligonucleotides in orthotopic GBM xenografts compared to normal brain tissue. The methodology used involves developing a quantitative method to differentiate oligonucleotide-induced gene silencing in GBM xenografts from gene silencing in normal brain tissue. A chemically diverse panel of oligonucleotides was tested, and the results showed that oligonucleotides optimized for pharmacological activity in normal brain tissue do not show consistent activity in GBM xenografts. The study then surveyed multiple advanced oligonucleotide chemistries for their activity in GBM xenografts, with lipid conjugates improving silencing in GBM cells across several different lipid classes. The primary objective of the study is to identify oligonucleotide conjugates that show promise for treating glioblastoma while minimizing neurotoxicity.

Comparative Analysis & Findings

  • The study found that oligonucleotides optimized for pharmacological activity in normal brain tissue do not show consistent activity in GBM xenografts. However, attaching lipid conjugates to oligonucleotides improves silencing in GBM cells across several different lipid classes. Highly hydrophobic lipid conjugates such as cholesterol and docosanoic acid enhance silencing but at the cost of higher neurotoxicity. Moderately hydrophobic, unsaturated fatty acid and amphiphilic lipid conjugates still improve activity without compromising safety. These oligonucleotide conjugates show promise for treating glioblastoma.

Implications and Future Directions

  • The study's findings suggest that oligonucleotide conjugates with lipid conjugates can improve silencing in GBM cells while minimizing neurotoxicity. Future research should focus on identifying the optimal lipid conjugate for oligonucleotide-based therapies for glioblastoma. Additionally, further studies should investigate the long-term safety and efficacy of these oligonucleotide conjugates in animal models and eventually in human patients.
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