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Tekmira, USAMRIID Publish Data Showing Ebola Protection in Primates Using SNALP RNAi Rx

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By Doug Macron

Tekmira Pharmaceuticals last week announced the publication of data showing that the company's proprietary nucleic acid-delivery technology could be used in conjunction with an RNAi drug to protect non-human primates from a lethal dose of Ebola virus.

The data, Tekmira President and CEO Mark Murray said in a statement, "are the first demonstration that RNAi is efficacious in an otherwise lethal primate infectious disease setting," and support the utility of RNAi in infectious diseases.

The study, which appeared in last week's issue of The Lancet, follows the publication of a report in 2006 in which researchers from Tekmira (then Protiva Biotherapeutics) and the US Army Medical Research Institute of Infectious Diseases showed that siRNAs, delivered using the company's stable nucleic acid lipid particles, could provide complete post-exposure protection from a lethal dose of Ebola virus in guinea pigs.

Looking to extend those findings to a more clinically relevant model, the partners examined the efficacy of such treatment in non-human primates, they wrote in The Lancet.

A cocktail of modified siRNAs targeting the Zaire Ebola virus L polymerase, viral protein 24, and viral protein 35 were formulated in SNALP molecules and administered to a group of rhesus macaques in 2 mg/kg intravenous infusions after 30 minutes, and on days 1, 3, and 5 following challenge with the virus. A second group of monkeys was given the same treatment at 30 minutes, and on days 1, 2, 3, 4, 5, and 6 after viral challenge.

According to the paper, the combination of the three siRNAs was expected to "aid in targeting potential RNA interference-escape mutants," while allowing the investigators to inactivate the virus in three different stages of its life cycle.

Two of the three monkeys that received the four post-exposure doses of the RNAi therapy were protected from lethal Ebola virus infection, while all of the animals receiving the seven doses were protected, the team wrote, providing "a model for the treatment of ZEBOV-induced hemorrhagic fever" and showing the potential of RNAi as an "effective post-exposure treatment strategy for people infected with the Ebola virus."

Noting that the systemic administration of synthetic siRNAs can potentially trigger toxic off-target effects that can distort the interpretation of data, the Tekmira and USAMRIID researchers tested the immunostimulatory activity of the SNALP formulation in mice and human cell culture.

"The ZEBOV cocktail was not immune stimulatory at the limit of sensitivity of the assays used," they wrote. These data, along with findings from 5′ RACE PCR experiments, "suggest that the antiviral effects in non-human primates are the result of specific RNA interference in reticuloendothelial cells and not due to immune stimulation or other off-target effects."

Additionally, the death of a macaque given a control siRNA treatment on day 10, which was "within the normal range of expected time to death for historical untreated controls, also suggests that the ZEBOV-mediated protection was specific to the siRNAs and not related to off-target effects," they added.

In The Lancet, the investigators noted that theirs was "a proof-of-concept study," and that the rhesus macaque model used "represents a worse-case scenario such as an accidental needle stick exposure of a laboratory worker or first responder to a high infectious dose of ZEBOV, which has occurred several times during the past five years."

ZEBOV infections in humans typically progress more slowly than in macaques, with fatality rates ranging from 70 percent to 90 percent, "suggesting that the therapeutic window could be larger than in experimentally infected macaques.

"Nonetheless, the focus in future studies will need to be on investigation of whether anti-ZEBOV siRNAs will be beneficial if administered at the onset of symptoms," they wrote.

Although the findings published last week represent "substantial progress" in the treatment of Ebola virus infections in non-human primates compared with previously reported post-exposure treatments that only resulted in partial protection, to develop a human therapy, studies will be required in guinea pig and non-human primate models of ZEBOV infection in accordance with the US Food and Drug Administration's guidelines for the assessment of treatments for Centers for Disease Control and Prevention category A threats, they added.

"Additionally, studies will need to be done to obtain data about pharmacology, dosing, and toxicology in uninfected non-human primates," they concluded.

Tekmira said it is continuing to work with collaborators to evaluate RNAi therapeutics targeting lethal hemorrhagic fever viruses, including Ebola virus, and that it has applied for additional US government funding to continue this work.

In 2006, the company received a $3.6 million grant from the US Defense Threat Reduction Agency to support the development of siRNA-based medicines for hemorrhagic fever viral infection, including Ebola virus (RNAi News 9/21/2006).

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