siRNA rescues nonhuman primates from advanced Marburg and Ravn virus disease

Area of Science:

• Virology
• Therapeutics Development
• RNA Interference

Background:

• Filoviruses, including Marburg virus (MARV) and Ravn virus (RAVV), are highly lethal pathogens with no current licensed vaccines or treatments.
• Developing broad-spectrum therapies is challenging due to significant sequence variability among marburgviruses.

Purpose of the Study:

• To evaluate the therapeutic efficacy of a single nucleoprotein-targeting (NP-targeting) small interfering RNA (siRNA) delivered via lipid nanoparticles (LNPs) against MARV and RAVV.
• To assess the effectiveness of this RNAi therapeutic in nonhuman primates with advanced-stage filovirus disease, mimicking critical patient care scenarios.

Main Methods:

• Lethally infected rhesus monkeys (n=16) with MARV or RAVV were treated with NP siRNA-LNP.
• Treatment initiation varied: 4 or 5 days post-infection for MARV, and 3 or 6 days post-infection for RAVV.

Main Results:

• All untreated control animals succumbed to filovirus infection.
• NP siRNA-LNP treatment resulted in 100% survival for RAVV-infected macaques, even with late-stage treatment initiation.
• MARV-infected animals showed 100% survival with treatment initiated on day 4 post-infection and 50% survival with treatment initiated on day 5 post-infection.

Conclusions:

• A single NP-targeting siRNA delivered by LNPs demonstrates broad-spectrum therapeutic efficacy against both MARV and RAVV.
• This RNAi therapeutic offers a potential solution for treating severe filovirus infections, including those with advanced disease stages.