For this purpose, this siRNA relies on complex chemical modification of the natural oligoribonucleotide in three main structural ways: (1) modification of every nucleoside with 2′-OMe or 2′-F moieties and terminal phosphorothioate (PS) linkages, (2) conjugation through a binary linker to (3), a trivalent N-acetylgalactosamine ligand for targeted delivery to hepatocytes. However, givosiran is administered as a nanoparticle-free solution. Patisiran is only modestly chemically modified and therefore depends on its lipid nanoparticle (LNP) encapsulation for nuclease protection and efficient tissue delivery. The clinical potential of this approach has been demonstrated through the recent approval of two siRNA therapeutics, patisiran and givosiran. Several groups have reported the use of a diverse set of chemically modified siRNAs for in vivo silencing. In its classical format, siRNAs are duplexes of 21 nucleotide (nt) RNA strands with a 19 nt complementary stem and a 2 nt overhang on the 3′-end of each strand. ![]() Small interfering RNAs (siRNAs) are one of the primary modalities in the field of RNA therapeutics, harnessing the endogenous RNA interference machinery for pharmacological interventions. The relatively straightforward design and predictable pharmacokinetic properties of oligonucleotides have enabled the development of a customized treatment for a single patient in <1 year, delivering on the promise of personalized medicine. A key advantage of this new drug class is its inherent potential to regulate the expression of any gene of interest through the rational design of a complementary oligonucleotide, including disease-causing genes that have been previously considered undruggable. Therapeutic oligonucleotides have emerged as a third pillar of modern pharmacotherapy, expanding the portfolio of traditional small molecule drugs and biologics. Furthermore, Lin28B is a promising target for cancers, and the development of such simplified siRNA analogs, possibly together with novel targeting units, holds potential. ![]() ![]() 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. ![]() Liver and kidney were the main sites of accumulation after its subcutaneous administration in mice. 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. 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. This structural complexity poses challenges for metabolite characterization and risk assessment after long-term patient exposure. 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.
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