Unified Nomenclature for RNAi Therapeutics Reflects Growing Advances in Gene Silencing

The recent approval of nedosiran has expanded the landscape of RNA interference (RNAi) therapeutics, bringing the total to 6 FDA-approved small interfering RNA (siRNA) treatments that utilize a common mechanism to target specific diseases, according to an article published in Molecular Pharmacology.

RNAi has emerged as a pivotal tool in gene regulation, allowing researchers to selectively manipulate gene expression. The primary forms of RNAi molecules include siRNAs and microRNAs (miRNAs), which interact with RNA-induced silencing complexes to regulate gene expression posttranscriptionally. These molecules can either degrade target mRNA or inhibit its translation, depending on their design and binding characteristics.

“In this minireview, we summarize the common and unique chemistry and molecular pharmacology of all six FDA-approved siRNA therapeutics and discuss the current and perplexing naming systems to support the use of a general and unified nomenclature of ‘RNAi’ therapeutic to align with the current therapeutic nomenclature criteria in pharmacology based on mechanism of action,” explained Gavin Traber and Ai-Ming Yu, Department of Biochemistry and Molecular Medicine, School of Medicine, University of California – Davis in Sacramento, California.

Among the 6 approved siRNA therapeutics, patisiran and vutrisiran are used for hereditary transthyretin-mediated amyloidosis, targeting the 3’ untranslated region (3’UTR) of the transthyretin mRNA. Clinical trials have shown significant reductions in serum transthyretin levels, with vutrisiran demonstrating improved liver-specific delivery. Lumasiran and nedosiran treat primary hyperoxaluria type 1 by targeting different mRNAs involved in oxalate production, while inclisiran addresses familial hypercholesterolemia and atherosclerotic cardiovascular disease by targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA. Givosiran uniquely targets the coding sequence of aminolevulinate synthase 1 (ALAS1), reducing neurotoxic metabolite levels in patients with acute hepatic porphyria.

The therapeutic effectiveness of these siRNAs is enhanced through various chemical modifications and delivery techniques, such as lipid nanoparticles or ligand conjugation for targeted distribution. Despite their differences in target sites and binding characteristics, 5 of the 6 therapeutics primarily act on the 3’UTR of their respective mRNAs, resembling miRNA mechanisms.

Given these complexities, there is a growing call for a unified nomenclature that categorizes these therapeutics under the broader term "RNAi therapeutics." This would better reflect their pharmacological actions rather than their specific chemical structures or sequence complementarity. Such a classification would streamline communication among researchers, clinicians, and patients while acknowledging the evolving nature of RNA-based therapies.

“We point out rather a surprisingly mechanistic action as miRNAs for five siRNA therapeutics and discuss the differences and similarities between siRNAs and miRNAs that supports using a general and unified term ‘RNAi’ therapeutics to align with current drug nomenclature criteria in pharmacology based on mechanism of action and embraces broader forms and growing number of novel RNAi therapeutics,” concluded the study authors.

References

Traber GM, Yu AM. The growing class of novel RNAi therapeutics. Mol Pharmacol. 2024;106(1):13-20. doi:10.1124/molpharm.124.000895