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Tekmira, Collaborators Report In Vivo Activity of siRNAs Against Marburg Virus

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Researchers from Tekmira Pharmaceuticals last week published new data showing that siRNAs targeting Marburg virus that have been formulated with the company's lipid nanoparticles could provide up to 100 percent post-exposure protection against infection in guinea pig models.

The work, Tekmira President and CEO Mark Murray said in a statement, builds off of the firm's ongoing clinical program in Ebola virus and lay "a foundation for future infectious disease therapeutics."

Marburg, like Ebola, is a filovirus that causes frequently fatal hemorrhagic fevers. The virus contains a single-stranded RNA genome encoding seven genes, which have been key targets for therapeutic intervention.

Having previously demonstrated that siRNAs delivered using its lipid nanoparticles could protect non-human primates from a lethal dose of Ebola virus — an effort that has yielded a phase I clinical candidate — Tekmira and collaborators at the University of Texas turned to Marburg to see if the RNAi approach could be effective against other filoviruses, the scientists wrote in the Journal of Infectious Diseases.

The team first designed 2'-O-methylated siRNAs against conserved regions of five Marburg virus genes for testing in vitro against a live strain of the virus.

In their paper, the investigators noted that a broad range of sequence variation exists between the different strains of Marburg, which "confounds the design of broad spectrum siRNA therapeutics" against the virus.

However, two genes — NP and VP24 — show a higher percentage of conserved contiguous bases that are "more amenable" to siRNA design. With an objective of developing an siRNA drug with the broadest spectrum activity against three or four Marburg strains, the researchers ultimately focused on siRNAs against NP and VP24, as well as VP35, VP40, and Lpol based on their potency and antisense sequence complementarity to key Marburg strains.

Tekmira and its collaborators selected five siRNA candidates — ones targeting Lpol, VP24, and VP40, and two against NP — for further evaluation, first testing their ability to induce an immune response in mice. After concluding that none of the siRNAs possessed a "significant immune stimulatory ability," they examined the drugs' in vivo activity.

The team used a recently developed Marburg guinea pig model, first focusing on the Angola strain of the virus, which was responsible for the largest and deadliest disease outbreak on record, according to the JID paper. Animals received either active drug, an siRNA control, or were left untreated.

Control animals showed clinical signs of Marburg infection with zero survival 6 to 8 days after viral challenge. A similar outcome was observed for those that received siRNAs against VP40 and VP24.

A 20 percent survival advantage was observed for guinea pigs receiving Lpol siRNAs. Meanwhile, one set of the anti-NP siRNAs — called NP-143m — was able to provide a 40 percent survival advantage to infected animals.

Most notably, the other set of NP-targeting siRNAs — called NP-718m — was able to confer a 100 percent survival advantage to infected animals, with only one of four guinea pigs tested showing signs of infection.

Encouraged by these data in Marburg-Angola, the researchers aimed to see if they could achieve protection across a broader spectrum of virus lineages, they wrote in their paper. To do so, they combined the two different NP-143m and NP-718m siRNAs into a single lipid nanoparticle, and treated guinea pigs that had been challenged with one of two other viral strains — Ci67 or Ravn.

Among animals challenged with Marburg-Ci67, controls were not treated and all died 8 to 12 days after challenge, while those receiving the siRNA cocktail experienced a 75 percent survival advantage. Interestingly, animals receiving NP-718m had 100 percent survival, in line with the data from the Marburg-Angola experiments. Animals receiving NP-143m showed 60 percent survival.

These survival data "suggested a dilutive effect" of mixing both NP-143m and NP-718m siRNAs, the investigators wrote. "However, given the small number of animals that were assessed it is difficult to conclude whether the cocktail treatment was less efficacious."

For the Marburg-Ravn animals, untreated controls all succumbed to the virus, while those receiving NP-718m treatment had a 60 percent survival rate. Those receiving NP-143m showed 75 percent survival.

All animals receiving the siRNA cocktail survived "despite the presence of a low-tolerance mismatch at position 9 in the NP-718m siRNA sequence against the NP mRNA sequence of MARV Ravn," they wrote in JID.

Next steps will include the examination of the siRNAs in non-human primates, the study's authors wrote.

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