Efficacy of a Novel Class of RNA Interference Therapeutic Agents

Abstract

RNA interference (RNAi) is being widely used in functional gene research and is an important tool for drug discovery. However, canonical double-stranded short interfering RNAs are unstable and induce undesirable adverse effects, and thus there is no currently RNAi-based therapy in the clinic. We have developed a novel class of RNAi agents, and evaluated their effectiveness in vitro and in mouse models of acute lung injury (ALI) and pulmonary fibrosis. The novel class of RNAi agents (nkRNA®, PnkRNA™) were synthesized on solid phase as single-stranded RNAs that, following synthesis, self-anneal into a unique helical structure containing a central stem and two loops. They are resistant to degradation and suppress their target genes. nkRNA and PnkRNA directed against TGF-β1mRNA ameliorate outcomes and induce no off-target effects in three animal models of lung disease. The results of this study support the pathological relevance of TGF-β1 in lung diseases, and suggest the potential usefulness of these novel RNAi agents for therapeutic application.

MicroRNA-29b Overexpression Decreases Extracellular Matrix mRNA and Protein Production in Human Corneal Endothelial Cells

“…The stem loop contained proline derivatives similar to PnkRNA, as previously described 29 . MiR-29b was transfected into iFECD using miR-29b Psh with lipofectamine RNAiMAX (Invitrogen, San Diego, CA) using standard protocols.…”

All-transretinoic acid ameliorates bleomycin-induced lung fibrosis by downregulating the TGF-β1/Smad3 signaling pathway in rats

“…Thus, RNAi-based therapy is already clinically applied; however, recommending this therapy to every patient remains difficult. 10 All-trans retinoic acid (ATRA), a derivative of vitamin A, exhibits a number of beneficial effects such as antiproliferative, anti-inflammatory, anti-migratory, and antifibrogenic activities. ATRA is currently used to induce remission in patients with acute promyelocytic leukemia and has the potential to be used to treat solid tumors.…”

siRNA Delivery to the lung: What's new?

“…PnkRNAs consist of an oligonucleotide that contains 2 proline derivatives and self-anneals to a structure of a central stem of the sense and antisense region, an unpaired part, and a loop. nkRNAs, on the other hand, self-anneals in absence of any proline derivatives into a central stem, a loop, and an unpaired site [34]. These novel RNAs have been used therapeutically in a model of acute lung injury [34] and in a lung cancer model, where mice were i.v.…”

“…nkRNAs, on the other hand, self-anneals in absence of any proline derivatives into a central stem, a loop, and an unpaired site [34]. These novel RNAs have been used therapeutically in a model of acute lung injury [34] and in a lung cancer model, where mice were i.v. injected with luciferase expressing A549-luc-C8 cells on day zero.…”