Background
Gene therapy is the approach that designed to introduce a genetic material (DNA or RNA) as a medicament to the patient. A number of viral-based vectors are used to deliver genes to correct a known mutation that causes a disease or modulate the immune response against cancer cells. Moreover, a therapeutic effect can also be achieved by targeting and inducing multiple pathways of programmed cell death. This strategy is beneficial for the treatment of heterogeneous tumors and its microenvironment, since inducing the cell death can cause a local anticancer response that is favorable to the patient and leads to a therapeutic effect. In addition to cancer, a similar strategy can be used to treat certain infectious diseases. The influenza A virus (IAV), usually persisting in wild birds and causing outbreaks of infection in domestic poultry, in some cases can cause a severe flu infection in humans. The prognosis for patients with avian flu is poor due to ineffective antiviral medication, frequent complications, and high death rate. Currently there are no effective vaccines against avian flu strains.
Summary
Investigation of the influenza A virus infection, accompanied by lysis of infected cells, led researchers from the Fox Chase Cancer Center to the discovery of proteins involved in regulation of a specific and immunogenic form of cell death, necroptosis. The DNA-dependent activator of interferonregulatory factors (DAI) protein recognize IAV genomic RNA and through the receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and the lineage kinase domain-like (MLKL) protein pathway triggers cell death and inflammatory responses. Consequently, the approach formed on viral-based targeted gene delivery of DAI, RIPK3 and MLKL, can accomplish the therapeutic response and reduce the volume of tumor or virally-infected cells. Likewise, targeting and promoting the clearance of IAV infected cells from the host by inducing cell death can be a new therapeutic cure for influenza. Thus, the administration of RNA virus vectors containing these genes can either be part of cancer therapy, or the treatment of a viral influenzainfection.
If the activity of DAI and/or RIPK3 contributes to the virulence of the virus, inhibiting DAI or RIPK3- induced cell death may benefit patients infected with a pandemic or virulent strain of the influenza virus. Therefore, in these cases, a patient infected with a pandemic or virulent strain of virus may be treated by administering inhibitors such as ponatinib or dabrafenib.
Thapa R.J. et al. DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death. Cell Host Microbe. 2016 Nov 9;20(5):674-681.
Patent and Publication Status: Patent pending. Publication # WO 2018/009541 A1.
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