Therapeutic siRNA: state of the art

Abstract

RNA interference (RNAi) is an ancient biological mechanism used to defend against external invasion. It theoretically can silence any disease-related genes in a sequence-specific manner, making small interfering RNA (siRNA) a promising therapeutic modality. After a two-decade journey from its discovery, two approvals of siRNA therapeutics, ONPATTRO ® (patisiran) and GIVLAARI™ (givosiran), have been achieved by Alnylam Pharmaceuticals. Reviewing the long-term pharmaceutical history of human beings, siRNA therapy currently has set up an extraordinary milestone, as it has already changed and will continue to change the treatment and management of human diseases. It can be administered quarterly, even twice-yearly, to achieve therapeutic effects, which is not the case for small molecules and antibodies. The drug development process was extremely hard, aiming to surmount complex obstacles, such as how to efficiently and safely deliver siRNAs to desired tissues and cells and how to enhance the performance of siRNAs with respect to their activity, stability, specificity and potential off-target effects. In this review, the evolution of siRNA chemical modifications and their biomedical performance are comprehensively reviewed. All clinically explored and commercialized siRNA delivery platforms, including the GalNAc (N-acetylgalactosamine)-siRNA conjugate, and their fundamental design principles are thoroughly discussed. The latest progress in siRNA therapeutic development is also summarized. This review provides a comprehensive view and roadmap for general readers working in the field.

High-quality RT-PCR with chemically modified RNA controls

“…Although in theory, RNAs (especially inactivated or recombinant viruses) are more appropriate as the positive controls, DNA positive controls are frequently chosen for commercial RT-PCR kits, due to their stability, economical efficiency and easy preparation. To enhance the stability of RNAs, many chemical modification strategies have been developed, such as 2’-modified functionality, 5’-phosphonate modification and locked nucleic acids[ 18 ]. However, it is unknown whether these stability-enhanced RNAs are appropriate as the positive controls.…”

“…Although canonical RNA is inherently unstable, the modified RNAs can be stable in nuclease resistance[ 17 ] and useful as potential therapeutics in disease treatment, such as hyperlipidemia, HCV, and others[ 18 ]. It is known that NTPαSe can be recognized by T7 RNA polymerase with high specificity and the transcribed phosphoroselenaote RNAs are nuclease-resistant [ [19] , [20] , [21] ].…”

Advances in targeted therapy for esophageal cancer

“…Compared with chemical drugs that need to recognize the complex spatial conformation of proteins, the use of siRNA to inhibit the growth of cancer cells is more precise and effective. 83 Development of a suitable carrier that delivers siRNA into cells is urgently needed to achieve precise positioning and regulation of target genes by siRNA. Moreover, analogs of oligonucleotides and pharmaceutical preparations synthesized in vitro can restore the expression of ncRNAs with tumor suppressor functions.…”

Cucurbiturils in nucleic acids research

“…siRNA represents a class of short doublestranded non-coding RNA molecules that participate in the RNA interference process, which is an important mechanism used by an organism to defend against external invasion by inhibiting the expression of specific genes. 98,99 The propensity of CB[n] to form stable inclusion complexes with charged guests was used to construct supramolecular polymeric nanostructures, which could electrostatically absorb siRNA and deliver it to cancer cells.…”