Combination treatment of mannose and GalNAc conjugated small interfering RNA protects against lethal Marburg virus infection.
Mol Ther
; 31(1): 269-281, 2023 01 04.
Article
em En
| MEDLINE
| ID: mdl-36114672
ABSTRACT
Marburg virus (MARV) infection results in severe viral hemorrhagic fever with mortalities up to 90%, and there is a pressing need for effective therapies. Here, we established a small interfering RNA (siRNA) conjugate platform that enabled successful subcutaneous delivery of siRNAs targeting the MARV nucleoprotein. We identified a hexavalent mannose ligand with high affinity to macrophages and dendritic cells, which are key cellular targets of MARV infection. This ligand enabled successful siRNA conjugate delivery to macrophages both in vitro and in vivo. The delivered hexa-mannose-siRNA conjugates rendered substantial target gene silencing in macrophages when supported by a mannose functionalized endosome release polymer. This hexa-mannose-siRNA conjugate was further evaluated alongside our hepatocyte-targeting GalNAc-siRNA conjugate, to expand targeting of infected liver cells. In MARV-Angola-infected guinea pigs, these platforms offered limited survival benefit when used as individual agents. However, in combination, they achieved up to 100% protection when dosed 24 h post infection. This novel approach, using two different ligands to simultaneously deliver siRNA to multiple cell types relevant to infection, provides a convenient subcutaneous route of administration for treating infection by these dangerous pathogens. The mannose conjugate platform has potential application to other diseases involving macrophages and dendritic cells.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Viroses
/
Marburgvirus
/
Doença do Vírus de Marburg
Limite:
Animals
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article