Biotechnological Evolution of siRNA Molecules: From Bench Tool to the Refined Drug

Abstract

The depth and versatility of siRNA technologies enable their use in disease targets that are undruggable by small molecules or that seek to achieve a refined turn-off of the genes for any therapeutic area. Major extracellular barriers are enzymatic degradation of siRNAs by serum endonucleases and RNAases, renal clearance of the siRNA delivery system, the impermeability of biological membranes for siRNA, activation of the immune system, plasma protein sequestration, and capillary endothelium crossing. To overcome the intrinsic difficulties of the use of siRNA molecules, therapeutic applications require nanometric delivery carriers aiming to protect double-strands and deliver molecules to target cells. This review discusses the history of siRNAs, siRNA design, and delivery strategies, with a focus on progress made regarding siRNA molecules in clinical trials and how siRNA has become a valuable asset for biopharmaceutical companies.

Influence of Sugar Modifications on the Nucleoside Conformation and Oligonucleotide Stability: A Critical Review

“…Oligonucleotide therapeutics have emerged as a very effective technique over the past few decades for the treatment of various diseases [1,2] . Small interfering RNAs (siRNAs), [3–13] microRNAs (miRNAs), [14,15] aptamers, [16,17] triplex‐forming oligonucleotides (TFO), [18,19] antisense oligonucleotides (AONs), [20,21] DNAzymes [22,23] are the leading candidates. These agents suppress the expression of different disease‐causing genes as they target the genes having complementary sequences through Watson‐Crick base pairing [24,25] .…”

“…These agents suppress the expression of different disease‐causing genes as they target the genes having complementary sequences through Watson‐Crick base pairing [24,25] . Among other functional oligonucleotides, siRNAs harness significant interest since there are four FDA‐approved siRNA drugs, and more than five siRNA candidates are currently being evaluated at advanced clinical trials [8,13] . The first siRNA drug patisiran was approved by FDA (August 2018) for a rare disease called Transthyretin‐Mediated Amyloidosis [26] .…”

“…Givosiran, inclisiran, lumisiran, and vutrisiran have also been approved by FDA in recent years as siRNA‐based therapies [27–30] . Other siRNA‐based drugs like fitusiran, teprasiran, cosdosiran, tivanisiran, nedosiran, cemdisiran are being evaluated under Phase 3 clinical trials [8,13] …”

Impact of Degree of Ionization and PEGylation on the Stability of Nanoparticles of Chitosan Derivatives at Physiological Conditions

“…Over the last decade, advances in RNA engineering have enabled the obtaining of small interfering RNAs (siRNA) with enhanced pharmacologic activities, which has driven an increased interest in establishing therapeutic platforms for the treatment of several diseases [ 1 ]. Despite improvements, the therapeutic efficiency of siRNA is still limited by the use of efficient vectors capable of directing them to their site of action, inside the target cells [ 2 ]. In this scenario, the use of non-viral vectors has gained prominence, especially after the use of lipid nanoparticles in mRNA vaccines applied in the fight against the Coronavirus Disease 2019 (COVID-19) pandemic [ 3 ] and for the transport of siRNA in the first RNA interference (RNAi) drug approved by the US Food and Drug Administration (FDA) in 2018 [ 2 ].…”

“…Despite improvements, the therapeutic efficiency of siRNA is still limited by the use of efficient vectors capable of directing them to their site of action, inside the target cells [ 2 ]. In this scenario, the use of non-viral vectors has gained prominence, especially after the use of lipid nanoparticles in mRNA vaccines applied in the fight against the Coronavirus Disease 2019 (COVID-19) pandemic [ 3 ] and for the transport of siRNA in the first RNA interference (RNAi) drug approved by the US Food and Drug Administration (FDA) in 2018 [ 2 ].…”