Open AccessPharmacodynamic and Pharmacokinetic Properties of Full Phosphorothioate Small Interfering RNAs for Gene Silencing In Vivo
Author(s) -
Christian Berk,
Gianluca Civenni,
Yuluan Wang,
Christian Steuer,
Carlo V. Catapano,
Jonathan Hall
Publication year - 2021
Publication title -
nucleic acid therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.255
H-Index - 67
eISSN - 2159-3345
pISSN - 2159-3337
DOI - 10.1089/nat.2020.0852
Subject(s) - small interfering rna , gene silencing , in vivo , linker , computational biology , pharmacology , in vitro , rna , rna interference , chemistry , biology , microbiology and biotechnology , biochemistry , gene , computer science , genetics , operating system
State-of-the-art small interfering RNA (siRNA) therapeutics such as givosiran and fitusiran are constructed from three variable components: a fully-modified RNA core that conveys metabolic stability, a targeting moiety that mediates target-cell uptake, and a linker. This structural complexity poses challenges for metabolite characterization and risk assessment after long-term patient exposure. In this study, we show that basic phosphorothioate modification of a siRNA targeting the oncoprotein Lin28B provides a useful increase in metabolic stability, without greatly compromising potency. We found that its stability in vitro matched that of nanoparticle-free patisiran in serum and surpassed it in liver tritosome extracts, although it did not reach the stability of the fitusiran siRNA core structure. Liver and kidney were the main sites of accumulation after its subcutaneous administration in mice. Despite the lack of a delivery agent-free antitumor effect, we anticipate our study to be a starting point to develop alternative siRNA scaffolds that can be degraded into naturally-occurring metabolites and help alleviate the aforementioned challenges. Furthermore, Lin28B is a promising target for cancers, and the development of such simplified siRNA analogs, possibly together with novel targeting units, holds potential.