Advances in siRNA therapeutics and synergistic effect on siRNA activity using emerging dual ribose modifications

Abstract

Nucleic acid-based therapeutics that control gene expression have been steadily progressing towards achieving their full clinical potential throughout the last few decades. Rapid progress has been achieved in RNAi-based therapy by optimizing high specificity and gene silencing efficiency using chemically modified siRNAs. Since 2018, four siRNA drugs - patisiran, givosiran, lumasiran, and inclisiran, were approved by the US FDA, providing a testament to the promise of RNAi therapeutics. Despite these promising results, safe and efficient siRNA delivery at the target site remains a major obstacle for efficient siRNA-based therapeutics. In this review, we have outlined the synergistic effects of emerging dual ribose modifications, including 2',4'- and 2',5'-modifications, 5'-E/Z-vinylphosphonate, and northern methanocarbacyclic (NMC) modifications that have contributed to drug-like effects in siRNA. These modifications enhance nuclease stability, prolong gene silencing efficiency, improve thermal stability, and exhibit high tissue accumulation. We also highlight the current progress in siRNA clinical trials. This review will help to understand the potential effects of dual ribose modifications and provides alternative ways to use extensive 2'-modifications in siRNA drugs. Moreover, the minimal number of these dual ribose modifications could be sufficient to achieve the desired therapeutic effect. In future, detailed in vivo studies using these dual ribose modifications could help to improve the therapeutic effects of siRNA. Rational design could further open doors for the rapid progress in siRNA therapeutics. [Figure: see text].

Keywords: RNAi clinical trial; gene silencing; siRNA; sugar modification; vinylphosphonate.

Figure 1.

Delivery platforms in siRNAs drugs in advance clinical trials. A. lipid nanoparticle (LNP) encapsulated siRNA B. GalNAc conjugation C. GalXC RNAi technology.

Figure 2.

Schematic representation of chemically modified siRNA strands for clinically approved siRNA drugs.

Figure 3.

Various C2’ and non-canonical sugar chemical modifications.

Figure 4.

Various 4’-thio-C2’ modifications.

Figure 5.

Various 4’/5’-aminoalkyl-C2’ modifications.

Figure 6.

C4’-Guanidino containing 2’ modifications.

Figure 7.

Various C4’-OMe/F/Me-C2ʹmodifications.

Figure 8.

5’-(E/Z)-Vinylphosphonate-C2’ modification.

Figure 9.

Various 2’,5’ dual modifications.

Figure 10.

Northern methanocarbacyclic and its fluorinated analogues.