Overcoming the challenges of tissue delivery for oligonucleotide therapeutics.

Autor: Gökirmak T; Department of Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Nikan M; Department of Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Wiechmann S; Department of Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Prakash TP; Department of Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Tanowitz M; Department of Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA., Seth PP; Department of Medicinal Chemistry, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA. Electronic address: PSeth@ionisph.com.
Jazyk: angličtina
Zdroj: Trends in pharmacological sciences [Trends Pharmacol Sci] 2021 Jul; Vol. 42 (7), pp. 588-604. Date of Electronic Publication: 2021 May 18.
DOI: 10.1016/j.tips.2021.04.010
Abstrakt: 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.
Competing Interests: Declaration of interests T.G., M.N., S.W., T.P.P, M.T., and P.P.S. are employees of Ionis Pharmaceuticals, Inc. at the time of writing the manuscript.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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