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Cited by 18RNA Interference and Gene DeliveryDNA and Nucleic Acid ChemistryGlioma Diagnosis and Treatment

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

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Sarli, Samantha L, Fakih, Hassan H, Kelly, Karen, Devi, Gitali, Rembetsy-Brown, Julia M, McEachern, Holly R, Ferguson, Chantal M, Echeverria, Dimas +5 more·2024·Nucleic Acids Research
DOI 10.1093/nar/gkae260PMC PMC11109979
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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.

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  • High local concentrations of cholesterol are toxic.

    “In addition to reducing penetration and delivery homogeneity, high local concentrations of cholesterol are toxic.26,27”

    From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [27]

    The Results section reports acute neurotoxicity in mice after intratumoral injection of cholesterol-conjugated siRNA, and the Discussion describes that conjugate as more neurotoxic than less hydrophobic alternatives (page unavailable). The paper does not establish that high local concentrations of cholesterol itself are toxic or test a concentration-dependent effect. (LLM, conf=0.86)

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Authors
Sarli, S. L., Fakih, H. H., Kelly, K., Devi, G., Rembetsy-Brown, J. M., McEachern, H. R., Ferguson, C. M., Echeverria, D., Lee, J., Sousa, J., Sleiman, H. F., Khvorova, A., & Watts, J. K.
Affiliations
  • University of Massachusetts Chan Medical School (US)
  • McGill University (CA)
Corresponding author
Watts, Jonathan K
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2024-04-13
Volume
52
Issue
9
Pages
4799-4817
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/gkae260
PMC
PMC11109979
OpenAlex
W4394785986
Cited by
18
References
5
Citations by year
2026: 5 · 2025: 9 · 2024: 4
FWCI
2.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Nucleic Acids Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • NIH (F31 CA261151, R01 NS111990, R01 NS104022, S10 OD020012)
  • American Cancer Society
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
Keywords
glioblastoma, antisense oligonucleotides, siRNA, oligonucleotide conjugates, lipid conjugates, gene silencing, orthotopic xenograft, oligonucleotide chemistry, cholesterol, docosanoic acid, neurotoxicity, brain tumor therapy
MeSH terms
Animals, Brain Neoplasms, Glioblastoma, Humans, Mice, Nude, Oligonucleotides, Antisense, Gene Silencing, Xenograft Model Antitumor Assays, RNA, Small Interfering, Cell Line, Tumor, Mice

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