Therapeutic Use of Artificially Generated Mononegavirales Defective Interfering Particles (DIP)
This technology includes using defective interfering (DI) genomes as a therapeutic against various mononegavirales. DI genomes are defective versions of the wildtype viral genome, incapable of replicating by itself but able to interfere with replication of the wildtype virus. We developed both a system to identify and characterize multiple naturally occurring henipaviruses Nipah (NiV) DI genomes species, and a methodology to artificially produce high titer stocks of virions containing these DI genomes, termed DI particles (DIPs). In vitro data showed that several of these DIPs were capable of reducing wildtype NiV titers by over 3-logs. Preliminary in vivo data using a small animal (hamster) disease model indicates efficacy of DIP treatment, with significantly improved survival rates in treated versus untreated animals, with a clear reduction or absence of clinical signs in the former group.
- DIPs are transmissible (in the presence of wildtype standard virus) and therefore able to disseminate, and target the same infected cells and tissues as the virus. The inherent targeting of DIPs to the analogous cells/tissues in a patient as the wildtype standard virus ensures that: a) the DIP will always likely be present in any virally-infected cell; and b) there will be no physiological compartment in the patient where virus could potential “hide” from the DIPs.
- Our data indicates that DIPs are able to activate the innate immune system, especially upregulation of interferon and RIG-I-like pathways. Therefore, as well as directly interfering with viral replication they are also able to interfere indirectly by priming an antiviral state.
- Our data indicates that both copyback- and deletion-type DI genome species are able to inhibit replication of wildtype standard virus. Deletion DI genomes are unique in that some retain the ability to express a protein. Therefore, any inherent inhibitory effects could be enhanced by encoding an immunogenic protein payload on the deletion DI genome, increasing its therapeutic potential.
- DIPs are unable to replicate unless in the presence of wildtype standard virus, and therefore likely to have minimal (if any) potential side effects.
- Unlike antivirals, DIPs will be much more resistant to escape mutants as any deleterious mutations potentially affecting the ability of the virus to replicate the DI genome will have analogous deleterious effects on wildtype standard virus replication. Secondly, the DIP treatment would be able to co-evolve alongside the wildtype standard virus, remaining effective throughout any future epidemics of disease for example.
- Unlike vaccine-mediated immunity via priming of the adaptive and innate immune pathways, DIP-mediated protection is effective straightaway. This would allow effective treatment of both the patient and any potential susceptible contacts to begin immediately after a diagnosis is either suspected or confirmed.