Transient Gene Therapy as Broad Spectrum Antiviral

项目总结

Project Summary Currently there are very few antiviral drugs, and no broad-spectrum antiviral drugs. For example, Influenza A virus (IAV) causes 12,000-56,000 deaths and 150,000-750,000 hospitalizations annually in the US alone, despite the availability of vaccines and five FDA-approved drugs 1, 2. Resistance to two of the five existing drugs has already emerged 13. Second, SARS-CoV-2 a virus which causes COVID19 led to unprecedented death toll worldwide. Currently there are no anti-SARS-Cov-2 drugs that can target other corona viruses. Type I interferons (IFNs) are host cytokines providing protection against viral infections. There are several different layers of IFN negative regulation, and the ISG15/USP 18 host protein 4, 5, 6, 7 complex is responsible for suppressing the tail end of IFN inflammation. Human ISG15 knockouts have been identified and shown to control IAV and SARS-CoV-2 replication better than WT counterparts. Based on the evidence of efficacy and safety provided by these ISG15-deficient individuals, Lab11 Therapeutics is developing new drugs, transient host-mimicking modified mRNA therapies aimed at enhancing control of IAV and SARS-CoV-2 infection in the general population 4, 6, 7. Candidate drugs are recreating antiviral state identified and tested in the human system, but, for FDA approval, Lab11 Therapeutics must demonstrate safety and efficacy in an animal model, before proceeding with human in vivo studies. This STTR aims to test our modRNA cocktail drugs in animal models of IAV and SARS-CoV2 infection. The phase I hypothesis is that modRNA cocktail delivered intranasally will restrict IAV replication in mice and SARS- CoV-2 infection in hamsters. We will test this hypothesis in Specific Aim 1, by evaluating the effects of modRNAs on IAV in human and murine cell lines followed by in vivo testing in mice. In Specific Aim 2, we will evaluate the effects modRNAs have on SARS-CoV-2 in human and hamster cell lines followed by in vivo testing in hamsters. In Phase II, we propose to test different delivery modes and encapsulations of modRNAs to optimize the most effective delivery and antiviral protection. The global influenza market is valued at about 5 billion dollars, about a fifth of which relates to non-vaccine products. The patient population targeted by Lab11 Therapeutics will be hundreds of millions of individuals in the general population. Given the crucial role of IFN in the control of many viral infections (ISG15-deficient cells control have been shown to control the replication of 14 different viruses more effectively than WT cells), the lead drugs developed here for IAV and SARS-CoV2 are likely to be effective against other viral diseases too. This will provide Lab11 Therapeutics with opportunities for the licensing of different products with identical mechanisms of action on an indication-by-indication basis.