RNA interference for the treatment of papillomavirus disease

Abstract

Human Papillomavirus (HPV)-induced diseases are a significant burden on our healthcare system and current therapies are not curative. Vaccination provides significant prophylactic protection but effective therapeutic treatments will still be required. RNA interference (RNAi) has great promise in providing highly specific therapies for all HPV diseases yet this promise has not been realised. Here we review the research into RNAi therapy for HPV in vitro and in vivo and examine the various targets and outcomes. We discuss the idea of using RNAi with current treatments and address delivery of RNAi, the major issue holding back clinical adoption. Finally, we present our view of a potential path to the clinic.

Keywords: Clinical trial; RNA interference; delivery; human papillomavirus; shRNA.; siRNA.

Fig. (1)

Schema of the RNAi pathway. Schematic representation of siRNA-mediated RNAi pathway (Degradation pathway). Chemically synthesised effector siRNAs can be directly delivered into the cell or else generated from the cleavage of longer double-stranded RNA (dsRNA) and/or intracellularly expressed short-hairpin RNA (shRNA) by the endonuclease, Dicer. The antisense or guide strand is loaded into the RISC to form the activated siRNA-RISC complex (siRISC), which associates with the target mRNA bearing complementarity to the guide siRNA. Finally, Argonaute 2 protein (Ago2), the core component of siRISC mediates cleavage of the transcript in the base-paired region. The cleaved mRNA is released and the RISC components are recycled to mediate further rounds of silencing.

Fig. (2)

A Timeline of HPV RNAi research. Studies into RNAi directed against high-risk papilloma types have facilitated significant progress towards a promising therapeutic since the first successful attempt at silencing E6/E7 in 2002.

Fig. (3)

Schema of Immune activation by siRNAs. RNA oligonucleotides and siRNAs are potent stimulators of the innate immune system, exerting their effects by activating endosomal toll-like receptors (TLRs), or the immunomodulatory proteins retinoic acid inducible gene (RIG)-I or Protein kinase R RNA-dependent protein kinase (PKR). This leads to the induction of interferon (IFN) and pro-inflammatory cytokines to promote an anti-viral state, which could be beneficial in a combined therapy against HPV disease.