Exploring the Mechanisms of FDA-Approved siRNA Treatments in Disease Therapy

Researchers published in Molecular Pharmacology explore the 6 US Food and Drug Administration (FDA)-approved small interfering ribonucleic acid (siRNA) treatments and how they are revolutionizing disease treatment by targeting gene expression at the posttranscriptional level. 

“The clinical use of RNA interference (RNAi) molecular mechanisms has introduced a novel, growing class of RNA therapeutics capable of treating diseases by controlling target gene expression at the posttranscriptional level,” said researchers. 

The FDA’s most recently approved siRNA treatment is nedosiran (Rivfloza). Five out of the 6 approved siRNA therapeutics act on the 3'-untranslated regions of target mRNAs rather than coding sequences. This mechanism closely mirrors the action of genome-derived microRNAs (miRNA). The 5 siRNA therapeutics with this common mechanism are patisiran (Onpattro), lumasiran (Oxlumo), inclisiran (Leqvio), vutrisiran (Amvuttra), and nedosiran.

Three FDA-approved siRNA therapeutics, including patisiran, givosiran, and nedosiran, degrade or cleave target mRNA through near-complete base-pair complementarity. These characteristics blur the line between siRNAs, miRNAs, and biosimilars, as they all play a role in the RNAi regulatory pathway. Moreover, the ability of these siRNA therapeutics to induce target mRNA degradation or cleavage challenges traditional distinctions between siRNAs and miRNAs. All 3 treatments converge in their action within the RNAi regulatory pathway, further complicating the differentiation process.

“The term ‘RNAi’ therapeutics coherently aligns with the growing number and various forms of novel RNAi therapeutics based on common pharmacological action and is more informative for professionals and the general public,” said researchers. 

Reference
Traber, Gavin M, and Yu, Ai-Ming. The growing class of novel RNAi therapeutics. Molecular Pharmacology. 2024;106 (1):13-20. doi: 10.1124/molpharm.124.000895