Infection-sensing minigenome as a novel therapeutic approach against Ebola virus

TL;DR

A new therapy uses virus proteins to fight Ebola by activating only in infected cells, reducing viral replication and spread.

Contribution

A novel infection-sensing minigenome therapy that activates only during viral infection to combat Ebola virus.

Findings

Therapeutic minigenomes suppressed EBOV RNA replication and protein production in infected cells.

A 50% reduction in reporter signal was observed in cells challenged with EBOV-like particles.

The minigenome approach shows potential for combating EBOV and other viral pathogens.

Abstract

We describe here a molecular therapy that uses the virus’s own proteins to combat itself. In this approach, infection-sensing RNAs encoding therapeutic genes are flanked by viral promoters and packaging signals in negative-sense orientation. These therapeutic minigenome RNAs do not express the transgene and remain silent in the absence of a viral infection. In contrast, if the cell is infected, the virus acts as a helper virus, providing viral proteins in trans to transcribe, replicate, and package the therapeutic minigenomes. Proof of concept for this therapeutic approach is demonstrated here using Ebola virus (EBOV) minigenomes expressing two antiviral transgenes: a short-hairpin (sh) RNA targeting the EBOV viral protein VP24 and an open-reading frame expressing a host peptide from the retinoblastoma-binding protein 6 (RBBP6). By using an EBOV tetracistronic-minigenome as a virus life cycle modeling system, we show here that both therapeutic minigenomes suppressed viral RNA replication and viral protein production, and a more than 50% reduction in the reporter signal was observed when cells were challenged with EBOV transcription/replication-competent virus-like particles. These findings highlight the therapeutic potential of infection-sensing minigenome to combat EBOV and perhaps other viral pathogens.

This work describes a novel antiviral therapeutic genetic payload to combat viruses. The therapeutic transgene is only expressed and amplified in viral infected cells. The payload is further amplified by viral infection to produce therapeutic particles that can spread to additional target cells to protect them against viral infection.

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