siRNA-based Therapeutics for Infectious Diseases

Small interfering RNAs (siRNAs) are either found in a variety of organisms or produced synthetically to target a specific mRNA in mammalian cells. They are usually 19-23 base pairs (bp) with 2-nucleotide (nt) 3' overhangs that mimic the natural products of the RNase III enzyme Dicer. It is generally accepted that siRNA duplexes less than 30 bp do not induce the antiviral interferon response. siRNAs are known to guide sequence-specific gene silencing of target mRNAs to which they are perfectly complementary by directing the RNA-induced silencing complex (RISC) to mediate site-specific cleavage, and, hence, destruction of the targeted mRNA. Exogenous siRNAs can also direct transcriptional gene silencing by inducing heterochromatin formation, leading to histone methylation and/or deacetylation, and ultimately DNA methylation.

Mechanism of RNA interference in mammalian cells. Figure 1. Mechanism of RNA interference in mammalian cells.

Infectious Diseases

siRNA-based therapy has emerged as a new biopharmaceutical platform for the treatment of a variety of disorders and many clinical trials have either been completed, are ongoing or have been approved for clinical application. Amongst these trials that have been dedicated to the treatment of infectious diseases, the majority of which have been focused on the treatment of viral infections, such as hepatitis B virus (HBV) and Ebola virus (EBOV).

  • ALN-HBV

    • Alnylam Pharmaceuticals is developing the ALN-HBV siRNA compound, currently in a phase 1/2 study. ALN-HBV targets a highly conserved sequence in the HBV X open reading frame which is downstream from an integration hotspot. The design of the study includes 3 parts: in healthy volunteers, a single ascending dose study and a multiple ascending dose study in chronic hepatitis B patients.

  • ARC-520

    • ARC-520 consists of a mixture of two liver-tropic cholesterol conjugated siRNAs-siHBV74 and siHBV77-targeting a region where all cccDNA-derived transcripts overlap. Therefore, ARC-520 should lead to the reduction of all viral antigens.

  • ARC-521

    • ARC-521 was another siRNA developed by Arrowhead Research Corporation in a phase 1 study. This compound targets both mRNA transcribed from HBV cccDNA and integrated DNA. Phase 1 was conducted in healthy volunteers and 11 HBeAg-negative CHB patients. ARC-521 was administered intravenously in this dose-escalating study. Potent reductions in HBsAg and HBV DNA were observed after ARC-521 dosing.

  • ARO-HBV

    • Arrowhead developed a novel agent, ARO-HBV, based on the Targeted RNAi Molecules (TRIM) delivery platform. ARO-HBV targets two triggers, one in X and the second in the S open reading frame of the HBV genome, which is also believed to decrease integration-derived HBsAg. This compound is undergoing further studies in a phase 1/2 clinical trial.

  • ARB-001467

    • ARB-001467 contains a mixture of three siRNA triggers targeting highly conserved regions on the four HBV RNA transcripts. ARB-001467 has been shown to inhibit the production of all HBV proteins and additionally to reduce cccDNA content. In one study, multiple injections administered to chimpanzees led to a 90% reduction of HBsAg levels and a 50% reduction of cccDNA within 28 days of treatment.

  • TKM-130803

    • TKM-130803 comprises two siRNA molecules siLpol-2 and siVP35 2 in a 1:1 mixture by weight and molarity. The two siRNAs silence expression of EBOV mRNA-dependent Lpolymerase (Lpol), and Viral Protein35 (VP35) respectively. The siRNAs enhance host-mediated viral mRNA destruction thereby inhibiting EBOV replication.

Reference

  1. Dyawanapelly, S.; et al. (2014). RNA interference-based therapeutics: molecular platforms for infectious diseases. Journal of Biomedical Nanotechnology. 10(9): 1998-2037.
For research use only. Not intended for any clinical use.