Overcoming the challenges of tissue delivery for oligonucleotide therapeutics. (July 2021)

• Record Type: Journal Article
• Authors: Gökirmak, Tufan; Nikan, Mehran; Wiechmann, Svenja; Prakash, Thazha P.; Tanowitz, Michael; Seth, Punit P.
• Is Part Of: Trends in pharmacological sciences. Volume 42:Number 7(2021)
• Page Start: 588
• Page End: 604
• Publication Date: 2021-07
• Subjects: antisense oligonucleotides (ASO) -- endocytic uptake and escape -- synthetic therapeutic oligonucleotides (STO) -- receptor-mediated drug delivery -- siRNA -- tissue distribution; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2021.04.010
• Languages: English
• ISSNs: 0165-6147

Abstract

Abstract : Synthetic therapeutic oligonucleotides (STO) represent the third bonafide platform for drug discovery in the pharmaceutical industry after small molecule and protein therapeutics. So far, thirteen STOs have been approved by regulatory agencies and over one hundred of them are in different stages of clinical trials. STOs hybridize to their target RNA or DNA in cells via Watson-Crick base pairing to exert their pharmacological effects. This unique class of therapeutic agents has the potential to target genes and gene products that are considered undruggable by other therapeutic platforms. However, STOs must overcome several extracellular and intracellular obstacles to interact with their biological RNA targets inside cells. These obstacles include degradation by extracellular nucleases, scavenging by the reticuloendothelial system, filtration by the kidney, traversing the capillary endothelium to access the tissue interstitium, cell-surface receptor-mediated endocytic uptake, and escape from endolysosomal compartments to access the nuclear and/or cytoplasmic compartments where their targets reside. In this review, we present the recent advances in this field with a specific focus on antisense oligonucleotides (ASOs) and siRNA therapeutics. Highlights: Synthetic therapeutic oligonucleotides (STOs) target genes and gene products by utilizing endogenous endonucleases for the degradation of cellular RNA, RNA maturation pathways by modulating splicing, and protein translation by sterically blocking the access of ribosomal machinery to mRNA. STOs cross at least two phospholipid bilayers, plasma, and endosomal membranes, to reach their biological targets, mRNA and DNA inside cells. They enter the cell through receptor-mediated endocytic uptake and escape endosomal compartments to access the cytoplasm and/or nucleus, where they exert pharmacological effects through different antisense mechanisms. Backbone and sugar modifications improve the drug properties of STOs by increasing their metabolic stability and affinity for plasma proteins to reduce glomerular filtration and urinary excretion, thereby facilitating distribution to peripheral tissues. Subsequent interactions with cell surface proteins promotes cellular internalization by endocytic pathways. Next-generation oligonucleotide drugs are targeted therapeutics conjugated to endogenous or exogenous ligands for cell-surface receptors expressed in specific cell types or tissues. Givosiran (Givlaari®) is the first ligand conjugated STO developed by Alnylam for the treatment of adults with acute hepatic porphyria.