ArticleMolecular therapy. Nucleic acids2019
Delivery of GalNAc-Conjugated Splice-Switching ASOs to Non-hepatic Cells through Ectopic Expression of Asialoglycoprotein Receptor.
Article in Molecular therapy. Nucleic acids, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 30 citations in OpenAlex.
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- Advanced siRNA delivery in combating hepatitis B virus: mechanistic insights and recent updates.Journal of nanobiotechnology · 2024Review
- Nucleic acid drugs: recent progress and future perspectives.Signal transduction and targeted therapy · 2024Review
- Multimodal imaging of a liver-on-a-chip model using labelled and label-free optical microscopy techniques.Lab on a chip · 2024Article
- Targeting and engineering long non-coding RNAs for cancer therapy.Nature reviews. Genetics · 2024Review
- How Driver Oncogenes Shape and Are Shaped by Alternative Splicing Mechanisms in Tumors.Cancers · 2023Review
- RNA splicing dysregulation and the hallmarks of cancer.Nature reviews. Cancer · 2023Review
- Splicing factor BUD31 promotes ovarian cancer progression through sustaining the expression of anti-apoptotic BCL2L12.Nature communications · 2022Article
- ASO-Based PKM Splice-Switching Therapy Inhibits Hepatocellular Carcinoma Growth.Cancer research · 2022Article
- PolyPurine Reverse Hoogsteen Hairpins Work as RNA Species for Gene Silencing.International journal of molecular sciences · 2021Article
- Alternative splicing and cancer: insights, opportunities, and challenges from an expanding view of the transcriptome.Genes & development · 2020Review
- Long non-coding RNAs in immune regulation and their potential as therapeutic targets.International immunopharmacology · 2020Review
- Hybridization-mediated off-target effects of splice-switching antisense oligonucleotides.Nucleic acids research · 2020Article
- The Evolving Druggability and Developability Space: Chemically Modified New Modalities and Emerging Small Molecules.The AAPS journal · 2020Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Splice-switching antisense oligonucleotides (ASOs) are promising therapeutic tools to target various genetic diseases, including cancer. However, in vivo delivery of ASOs to orthotopic tumors in cancer mouse models or to certain target tissues remains challenging. A viable solution already in use is receptor-mediated uptake of ASOs via tissue-specific receptors. For example, the asialoglycoprotein receptor (ASGP-R) is exclusively expressed in hepatocytes. Triantennary N-acetylgalactosamine (GalNAc) (GN3)-conjugated ASOs bind to the receptor and are efficiently internalized by endocytosis, enhancing ASO potency in the liver. Here we explore the use of GalNAc-mediated targeting to deliver therapeutic splice-switching ASOs to cancer cells that ectopically express ASGP-R, both in vitro and in tumor mouse models. We found that ectopic expression of the major isoform ASGP-R1 H1a is sufficient to promote uptake and increase GN3-ASO potency to various degrees in four of five tested cancer cells. We show that cell-type-specific glycosylation of the receptor does not affect its activity. In vivo, GN3-conjugated ASOs specifically target subcutaneous xenograft tumors that ectopically express ASGP-R1, and modulate splicing significantly more strongly than unconjugated ASOs. Our work shows that GN3-targeting is a useful tool for proof-of-principle studies in orthotopic cancer models, until endogenous receptors are identified and exploited for efficiently targeting cancer cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.