Beyond GalNAc! Drug delivery systems comprising complex oligosaccharides for targeted use of nucleic acid therapeutics

O'Sullivan, Joseph; Muñoz‐Muñoz, José Luis; Turnbull, Graeme; Sim, Neil; Penny, Stuart; Moschos, Sterghios A.

doi:10.1039/d2ra01999j

Cited by 10 publications

(5 citation statements)

References 190 publications

(237 reference statements)

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“… 16 , 17 Since then, ligand-siRNA conjugates have emerged as another siRNA-based modality, also resulting in approved RNAi therapies. 18 These conjugates are compatible with subcutaneous administration and generally more stable than LNP-siRNA, which is preferred in less developed countries and tropical climates. However, the well-adopted N-acetylgalactosamine (GalNAc)-siRNA conjugates deliver payloads predominantly via the asialoglycoprotein receptor (ASGPR), which is highly expressed on hepatocytes but minimally on other cell types.…”

Section: Introductionmentioning

confidence: 99%

Combination treatment of mannose and GalNAc conjugated small interfering RNA protects against lethal Marburg virus infection

Ye¹,

Holland²,

Wood³

et al. 2023

Molecular Therapy

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Section: Introductionmentioning

confidence: 99%

Combination treatment of mannose and GalNAc conjugated small interfering RNA protects against lethal Marburg virus infection

Ye¹,

Holland²,

Wood³

et al. 2023

Molecular Therapy

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“…GalNAc-based delivery relies on the ability of the hepatocytes to express the asialoglycoprotein receptor, a high-capacity, rapidly internalizing receptor that binds glycoproteins via receptor-mediated endocytosis. In recent years, encouraging progress has been made in the field of GalNAc conjugates, underscoring the value of targeting moieties. , The conjugation of GalNAc moieties to oligonucleotides represents a promising and safe approach for liver-targeted delivery of nucleic acid therapeutics.…”

Section: Outlook and Perspectivesmentioning

confidence: 99%

“…In recent years, encouraging progress has been made in the field of GalNAc conjugates, underscoring the value of targeting moieties. 89 , 90 The conjugation of GalNAc moieties to oligonucleotides represents a promising and safe approach for liver-targeted delivery of nucleic acid therapeutics.…”

Section: Outlook and Perspectivesmentioning

confidence: 99%

Messenger RNA-Based Therapeutics and Vaccines: What’s beyond COVID-19?

Liu

et al. 2023

ACS Pharmacol. Transl. Sci.

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With the rapid success in the development of mRNA vaccines against COVID-19 and with a number of mRNAbased drugs ahead in the pipelines, mRNA has catapulted to the forefront of drug research, demonstrating its substantial effectiveness against a broad range of diseases. As the recent global pandemic gradually fades, we cannot stop thinking about what the world has gained: the realization and validation of the power of mRNA in modern medicine. A significant amount of research has now been concentrated on developing mRNA drugs and vaccine platforms against infectious and immune diseases, cancer, and other debilitating diseases and has demonstrated encouraging results. Here, based on the CAS Content Collection, we provide a landscape view of the current state, outline trends in the research and development of mRNA therapeutics and vaccines, and highlight some notable patents focusing on mRNA therapeutics, vaccines, and delivery systems. Analysis of diseases disclosed in patents also reveals highly investigated diseases for treatments with these medicines. Finally, we provide information about mRNA therapeutics and vaccines in clinical trials. We hope this Review will be useful for understanding the current knowledge in the field of mRNA medicines and will assist in efforts to solve its remaining challenges and revolutionize the treatment of human diseases.

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“…[13] Indeed, this receptor is a carbohydrate-binding protein that recognizes and binds N-acetylgalactosamine (GalNAc) or galactose residues. [14,15] By engineering rAAV vectors to recognize and bind to ASGPR, the specificity of gene expression in hepatocytes could be enhanced. [16,17] This targeted approach holds great potential to treat genetic or metabolic disorders in the liver, with improved therapeutic precision and safety.…”

Section: Introductionmentioning

confidence: 99%

Advancing Liver Gene Therapy: Enhanced Transduction with GalNAc-Bioconjugated rAAV Capsids

Lalys,

Bourdon,

Bouzelha

et al. 2024

Preprint

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This study investigates novel approaches to improve targeted gene delivery to the liver, a crucial organ for metabolic processes that faces vulnerabilities from various pathologies. Adeno-associated virus (AAV)-based gene therapy has emerged as a promising approach for liver targeting, with numerous investigational avenues. However, administration of high doses of AAV vectors present safety concerns, often requiring the use of corticosteroids and immunosuppression to mitigate immune adverse events. To address this, substantial efforts are underway to engineer optimized capsids to enhance the efficiency and specificity of recombinant AAV (rAAV) targeting hepatocytes, aiming to reduce required dosages. In this study, we employed bioconjugation chemistry to target the Asialoglycoprotein receptor (ASGPR), a C-type lectin abundantly expressed at the surface of hepatocyte membranes. We demonstrated that covalently attaching carbohydrates derived from GalNAc (a known ASGPR ligand) to lysine amino-acids on the rAAV2 capsid significantly enhanced in vivo liver transduction efficiency in mice. These optimized vectors present a promising avenue for the treatment of a spectrum of liver diseases, providing an alternative solution within the framework of liver gene therapy.

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Beyond GalNAc! Drug delivery systems comprising complex oligosaccharides for targeted use of nucleic acid therapeutics

Abstract: Tapping the glycome space for targeted delivery. We explore GalNAc for targeting oligonucleotides to the liver and ask what other oligosaccharides could expand targeting options for other tissues.

Cited by 10 publications

References 190 publications

Combination treatment of mannose and GalNAc conjugated small interfering RNA protects against lethal Marburg virus infection

Combination treatment of mannose and GalNAc conjugated small interfering RNA protects against lethal Marburg virus infection

Messenger RNA-Based Therapeutics and Vaccines: What’s beyond COVID-19?

Advancing Liver Gene Therapy: Enhanced Transduction with GalNAc-Bioconjugated rAAV Capsids

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