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siRNA-Conjugates prevent Marburg virus disease

The treatment with mannose and GalNAc conjugated small interfering RNA protects against lethal Marburg virus infection.

To prevent Marburg virus disease, Ye et al. recently identified a hexavalent mannose ligand with a high affinity to macrophages and dendritic cells. Both cells are key cellular targets of the Marburg virus (MARV). The research group developed a siRNA conjugate platform for successful subcutaneous delivery of siRNAs targeting the MARV nucleoprotein.

For selective delivery of siRNA therapeutic drugs to targets inside cells, siRNA drugs must overcome cellular defenses that keep invading RNAs outside cells.

In recent years, medicinal scientists developed a wide array of delivery methodologies. One crucial and successful approach was the development of N-acetylgalactosamine (GalNAc) siRNA conjugates for selective delivery to the liver. GalNAc-siRNA conjugates solved the siRNA delivery problem for liver hepatocytes. Tris-GalNAc binds to the hepatocyte's Asialoglycoprotein receptor resulting in rapid endocytosis.


The new approach utilized two ligands to deliver siRNA to multiple cell types. The ligands enabled the successful delivery of siRNA conjugates to macrophages in vitro and in vivo to achieve gene silencing. An endosome release polymer functionalized with mannose supported the Hexa-mannose-siRNA conjugate. This approach provides a subcutaneous route of administration for treating infection by these dangerous pathogens.


The siRNA conjugate treatment achieved 100% protection against the lethal MARV infection in the guinea pig model.


Marburg virus disease causes hemorrhagic fever with a fatality ratio of up to 88 percent. Two outbreaks in Marburg and Frankfurt in Germany and Belgrade, Serbia, in 1967 led to the discovery of the disease. The Marburg virus is in the same family as the Ebola virus. 
More prolonged exposure to the Marburg virus in mines or caves inhabited by Rousettus bat colonies resulted in the disease. After infecting an individual, the virus spreads through human-to-human transmission via direct contact, for example, through broken skin or mucous membranes, with the blood, secretions, organs, or other bodily fluids of infected people, and also with surfaces and materials such as bedding, and clothing contaminated with these fluids.

Marburg virus (MARV) is a negatively stranded RNA virus transmitted to humans from infected animals such as bats and nonhuman primates. The virus targets the mononuclear phagocyte system, macrophages, monocytes, Kupffer cells, and dendritic cells. Cells, such as hepatocytes and fibroblast-like cells, are also targeted by the virus. (Ye et al., 2022).

The genome of the virus is a 19-kb RNA encoding seven viral proteins, including nucleoprotein (NP), VP35 (polymerase cofactor), VP40 (matrix protein), glycoprotein (GP), VP30 (transcription activator), VP24 (secondary matrix protein), and an RNA-dependent RNA polymerase (L polymerase). All are potential targets for the development of anti-MARV therapies.

Reference

GalNAc

Ye X, Holland R, Wood M, Pasetka C, Palmer L, Samaridou E, McClintock K, Borisevich V, Geisbert TW, Cross RW, Heyes J. Combination treatment of mannose and GalNAc conjugated small interfering RNA protects against lethal Marburg virus infection. Mol Ther. 2022 Sep 15:S1525-0016(22)00563-9.  [
Molecular Therapy]

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