Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics

Huang, Yuanyu

doi:10.1016/j.omtn.2016.12.003

Cited by 233 publications

(215 citation statements)

References 107 publications

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“…GalNAc is a well‐known liver‐targeted ligand with high affinity to asialoglycoprotein receptor (ASGPR) (Figure A) . Modifications of oligonucleotides with mono‐, di‐, tri‐, or tetra‐GalNAc can improve the delivery efficiency of oligonucleotide drugs to hepatocytes.…”

Section: Chemically Modified Nucleic Acid Drugs For Target Specific Imentioning

confidence: 99%

Chemical modifications of nucleic acid drugs and their delivery systems for gene‐based therapy

Chen

Yang

Tang

2018

Medicinal Research Reviews

121

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Gene-based therapy is one of essential therapeutic strategies for precision medicine through targeting specific genes in specific cells of target tissues. However, there still exist many problems that need to be solved, such as safety, stability, selectivity, delivery, as well as immunity. Currently, the key challenges of gene-based therapy for clinical potential applications are the safe and effective nucleic acid drugs as well as their safe and efficient gene delivery systems. In this review, we first focus on current nucleic acid drugs and their formulation in clinical trials and on the market, including antisense oligonucleotide, siRNA, aptamer, and plasmid nucleic acid drugs. Subsequently, we summarize different chemical modifications of nucleic acid drugs as well as their delivery systems for gene-based therapeutics in vivo based on nucleic acid chemistry and nanotechnology methods.

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Section: Chemically Modified Nucleic Acid Drugs For Target Specific Imentioning

confidence: 99%

Chemical modifications of nucleic acid drugs and their delivery systems for gene‐based therapy

Chen

Yang

Tang

2018

Medicinal Research Reviews

121

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“…Researchers have also managed to deliver therapeutic microRNAs to hepatocytes by tagging the oligonucleotides with N-acetylgalactosamine, making it efficiently endocytosed by the hepatocyte-specific asialoglycoprotein receptor [67]. This shows that, similar to advances in viral gene therapy, non-viral vectors can also be improved with a ‘pseudotype’ to increase their efficacy and specificity.…”

Section: A Brief History Of In-vivo Gene Therapymentioning

confidence: 99%

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Haasteren

Hyde

Gill

2018

Expert Opinion on Biological Therapy

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Introduction: Ex-vivo gene therapy has had significant clinical impact over the last couple of years and in-vivo gene therapy products are being approved for clinical use. Gene therapy and gene editing approaches have huge potential to treat genetic disease and chronic illness. Areas covered: This article provides a review of in-vivo approaches for gene therapy in the lung and liver, exploiting non-viral and viral vectors with varying serotypes and pseudotypes to target-specific cells. Antibody responses inhibiting viral vectors continue to constrain effective repeat administration. Lessons learned from ex-vivo gene therapy and genome editing are also discussed. Expert opinion: The fields of lung and liver in-vivo gene therapy are thriving and a comparison highlights obstacles and opportunities for both. Overcoming immunological issues associated with repeated administration of viral vectors remains a key challenge. The addition of targeted small molecules in combination with viral vectors may offer one solution. A substantial bottleneck to the widespread adoption of in-vivo gene therapy is how to ensure sufficient capacity for clinical-grade vector production. In the future, the exploitation of gene editing approaches for in-vivo disease treatment may facilitate the resurgence of non-viral gene transfer approaches, which tend to be eclipsed by more efficient viral vectors.

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“…It is likely that GalNAc-siRNA conjugates will eventually replace most therapeutic LNP efforts for liver targets. GalNAc conjugates have also been adapted for liver delivery of ASOs and antagomirs, which are currently in early phase clinical trials 80–82 .…”

Section: Delivery Of Sirna-based Drugsmentioning

confidence: 99%

“…Targeted gene knockdown is also likely to reduce bystander cell toxicity and require lower doses. The same strategies that deliver siRNAs to the liver or elsewhere in the body can also be employed to deliver miRNA mimics, either as stem-loops or as double-stranded ~22-nucleotide modified RNAs that resemble the endogenous Dicer-cleaved miRNA 80,95 . The lessons learned about delivering siRNAs will probably facilitate the development of ways to deliver the larger cargo being contemplated for therapeutics using modified mRNAs 96,97 or CRISPR-Cas-mediated gene editing 98–104 .…”

Section: Delivery Of Sirna-based Drugsmentioning

confidence: 99%

Tapping the RNA world for therapeutics

Lieberman

2018

Nat Struct Mol Biol

156

127

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A recent revolution in RNA biology has led to the identification of new RNA classes with unanticipated functions, new types of RNA modifications, an unexpected multiplicity of alternative transcripts and widespread transcription of extragenic regions. This development in basic RNA biology has spawned a corresponding revolution in RNA-based strategies to generate new types of therapeutics. Here, I review RNA-based drug design and discuss barriers to broader applications and possible ways to overcome them. Because they target nucleic acids rather than proteins, RNA-based drugs promise to greatly extend the domain of ‘druggable’ targets beyond what can be achieved with small molecules and biologics.

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Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics

Cited by 233 publications

References 107 publications

Chemical modifications of nucleic acid drugs and their delivery systems for gene‐based therapy

Chemical modifications of nucleic acid drugs and their delivery systems for gene‐based therapy

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Tapping the RNA world for therapeutics

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