Harnessing defective interfering particles and lipid nanoparticles for effective delivery of an anti-dengue virus RNA therapy

Lin, M.-H.; Maniam, P.; Li, D.; Tang, B.; Bishop, C.; Suhrbier, A.; Wales-Earl, L.; Tayyar, Y.; McMillan, N. A. J.; Li, L.; Harrich, D.

doi:10.1101/2024.04.23.590664

bioRxiv · 10.1101/2024.04.23.590664

Harnessing defective interfering particles and lipid nanoparticles for effective delivery of an anti-dengue virus RNA therapy

Lin, M.-H.·Maniam, P.·Li, D.·Tang, B.·Bishop, C.·Suhrbier, A.·Wales-Earl, L.·Tayyar, Y.·McMillan, N. A. J.·Li, L.·Harrich, D.

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Abstract

Presently, no approved antiviral drug targets dengue virus (DENV) infection. Treatment mainly relies on supportive measures, while DENV vaccines efficacy varies based on factors like vaccine type, circulating DENV serotypes and vaccinated population. This study explores using defective interfering particles (DIPs) and lipid nanoparticles (LNPs) to deliver an anti-DENV defective interfering RNA, known as DI290. Results showed that both DIPs and DI290 loaded LNPs (LNP-290) effectively suppressed DENV infection in human primary monocyte-derived macrophages (MDMs), THP-1 macrophages and human fibroblasts, representing cell types naturally targeted by DENV. Furthermore, LNP-290 demonstrated >log10 inhibition of DENV viral loads in IFNAR-deficient mice, which lack functional type I interferon (IFN) receptors. DI290-mediated inhibition was also effective in IFN regulatory factor 3 and 7 double knockout mice. RNA-Seq data from LNP-treated C57BL/6J mice, IFNAR-deficient mice and human MDMs treated with LNPs or DENV DIPs illustrated DI290 treatment heightened IFN responses, particularly IFN{gamma}, as well as IFN/{beta} and IFN{lambda}. DI290 thus induces a broad range of IFN responses, with IFN{gamma} and IFN{lambda} providing anti-viral activity when IFN/{beta} responses are absent. Mice administered LNP-290 also did not manifest acute overt clinical signs. In summary, these experiments suggest DI290s potential as a therapeutic approach for combating DENV infection.

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Lin, M.-H., Maniam, P., Li, D., Tang, B., Bishop, C., Suhrbier, A., Wales-Earl, L., Tayyar, Y., McMillan, N. A. J., Li, L., Harrich, D.. 2024-04-23. Harnessing defective interfering particles and lipid nanoparticles for effective delivery of an anti-dengue virus RNA therapy. https://doi.org/10.1101/2024.04.23.590664

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