N-Acetyl Galactosamine Targeting: Paving the Way for Clinical Application of Nucleotide Medicines in Cardiovascular Diseases

E.A.L. Biessen, T.J.C. Van Berkel*

*Corresponding author for this work

Research output: Contribution to journal(Systematic) Review article peer-review

2 Citations (Web of Science)

Abstract

While the promise of oligonucleotide therapeutics, such as (chemically modified) ASO (antisense oligonucleotides) and short interfering RNAs, is undisputed from their introduction onwards, their unfavorable pharmacokinetics and intrinsic capacity to mobilize innate immune responses, were limiting widespread clinical use. However, these major setbacks have been tackled by breakthroughs in chemistry, stability and delivery. When aiming an intervention hepatic targets, such as lipid and sugar metabolism, coagulation, not to mention cancer and virus infection, introduction of N-acetylgalactosamine aided targeting technology has advanced the field profoundly and by now a dozen of N-acetylgalactosamine therapeutics for these indications have been approved for clinical use or have progressed to clinical trial stage 2 to 3 testing. This technology, in combination with major advances in oligonucleotide stability allows safe and durable intervention in targets that were previously deemed undruggable, such as Lp(a) and PCSK9 (proprotein convertase subtilisin/kexin type 9), at high efficacy and specificity, often with as little as 2 doses per year. Their successful use even the most visionary would not have predicted 2 decades ago. Here, we will review the evolution of N-acetylgalactosamine technology. We shall outline their fundamental design principles and merits, and their application for the delivery of oligonucleotide therapeutics to the liver. Finally, we will discuss the perspectives of N-acetylgalactosamine technology and propose directions for future research in receptor targeted delivery of these gene medicines.
Original languageEnglish
Pages (from-to)2855-2865
Number of pages11
JournalArteriosclerosis Thrombosis and Vascular Biology
Volume41
Issue number12
DOIs
Publication statusPublished - 1 Dec 2021

Keywords

  • asialoglycoproteins
  • galactose
  • hypertension
  • ligand
  • oligonucleotide
  • TRANSFER PROTEIN EXPRESSION
  • PEPTIDE NUCLEIC-ACID
  • ASIALOGLYCOPROTEIN RECEPTOR
  • IN-VIVO
  • ANTISENSE OLIGONUCLEOTIDES
  • MANNOSE RECEPTOR
  • BINDING PEPTIDE
  • HIGH-AFFINITY
  • DELIVERY
  • SIRNA

Cite this