Protection against lethal Marburg virus infection mediated by lipid encapsulated small interfering RNA.

Abstract

BACKGROUND:

Marburg virus (MARV) infection causes severe morbidity and mortality in humans and nonhuman primates. Currently, there are no licensed therapeutics available for treating MARV infection. Here, we present the in vitro development and in vivo evaluation of lipid-encapsulated small interfering RNA (siRNA) as a potential therapeutic for the treatment of MARV infection.

METHODS:

The activity of anti-MARV siRNAs was assessed using dual luciferase reporter assays followed by in vitro testing against live virus. Lead candidates were tested in lethal guinea pig models of 3 different MARV strains (Angola, Ci67, Ravn).

RESULTS:

Treatment resulted in 60%-100% survival of guinea pigs infected with MARV. Although treatment with siRNA targeting other MARV messenger RNA (mRNA) had a beneficial effect, targeting the MARV NP mRNA resulted in the highest survival rates. NP-718m siRNA in lipid nanoparticles provided 100% protection against MARV strains Angola and Ci67, and 60% against Ravn. A cocktail containing NP-718m and NP-143m provided 100% protection against MARV Ravn.

CONCLUSIONS:

These data show protective efficacy against the most pathogenic Angola strain of MARV. Further development of the lipid nanoparticle technology has the potential to yield effective treatments for MARV infection.

• Authors: Raul Ursic-Bedoya, Chad E Mire, Marjorie Robbins, Joan B Geisbert, Adam Judge, Ian MacLachlan, Thomas W Geisbert
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 209 Issue 4 Pg. 562-70 (Feb 15 2014) ISSN: 1537-6613 [Electronic] United States
• PMID: 23990568 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Carrier Proteins
• Cytokines
• Drug Carriers
• Ifit1 protein, mouse
• Lipids
• RNA, Small Interfering
• RNA-Binding Proteins

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Carrier Proteins (analysis)
• Cytokines (blood)
• Drug Carriers (chemistry)
• Female
• Genes, Viral
• Guinea Pigs
• Lipids (administration & dosage, chemistry)
• Liver (chemistry)
• Marburg Virus Disease (drug therapy, genetics, metabolism, prevention & control)
• Marburgvirus (drug effects, genetics)
• Mice
• Mice, Inbred ICR
• Nanoparticles (administration & dosage, chemistry)
• RNA, Small Interfering (administration & dosage, chemistry)
• RNA-Binding Proteins
• Survival Analysis
• Viral Load