Sunday, July 15, 2007

Can RNAi Therapeutics do a Better than Monoclonal Antibodies in RSV Infection?

Arguably, the next main proof point that looms for RNAi Therapeutics is proof-of-concept that RNAi can be made to work in humans. Alnylam takes its first shot at this in their randomised, placebo-controlled, double-blinded phase II study for the treatment of respiratory syncytial virus (RSV) infection. In this study, volunteers infected with an attenuated form of RSV will be treated with ALN-RSV01, an siRNA targeting a conserved region of the nucleocapsid (N) protein mRNA, and its effect on viral load and symptoms evaluated. Results from this trial, initiated last month (see Blog from 25 June 07: “Alnylam Progresses RSV RNAi Program into Phase II Clinical Studies”) are expected by the end of this year.

Currently, the only effective drugs in addressing RSV are neutralising antibodies that were developed by MedImmune (now AstraZeneca). These monoclonal antibodies (MAb) are directed against the F-protein on the surface of RSV and block cellular entry of the virus. Importantly, whereas these MAbs are used for the prevention of RSV infection in a small at-risk population, premature infants, ALN-RSV01 is geared towards the treatment of RSV.

Numerous studies have shown that the effect of RNAi, and probably any type of drug, on viral replication is most potent when given around the time of infection. I therefore wondered why ALN-RSV01 should succeed in the treatment of RSV when other drug classes such as MAbs have failed. Indeed, my own literature research confirms that MAbs have been tested in animal models for the treatment of RSV, but were found to lack sufficient therapeutic activity.

A study by Mejia et al. [Antimicrobial Agents and Chemotherapy 49: 4700 (2005)] compares 50mg/kg of the latest generation of anti-RSV MAbs when given either before or after viral infection in mice, and finds that on almost all accounts (viral load, inflammation, lung pathology) MAbs were only effective when given shortly (24 hours) before infection. The only assay that showed an effect when MAbs were given 48 hours after infection was a viral plaque forming assay which may reflect the presence of neutralising antibodies in the assay.

Bitko et al. [Nature Medicine 11:50 (2005)] on the other hand showed in an almost identical mouse model that intranasally delivered siRNAs had a profound effect on RSV replication even when given after viral infection. Moreover, 3.5mg/kg doses already proved very effective. Importantly, siRNAs were able to limit viral replication even when given up to 5 days after viral infection, the time when the acute phase of RSV peaks in this particular model. This is crucial in the clinical setting where the treatment benefit will likely be optimal if RNAi therapy can be initiated before acute infection has peaked. The authors then go on to show that on a number of counts (respiratory rate, pathology score, leukotriene production), anti-RSV siRNAs almost abolished any pathological signs of the disease.

These results suggest that while current MAbs are potent in reducing the initial infection by neutralising the interaction of the virus with the host cell, they are ineffective in preventing the subsequent spread of the virus. This could be due to the kinetics of viral re-infection in close proximity to the next host cell. By contrast, unless they target host surface receptors, siRNAs will not be able to prevent viral infection. The can, however, prevent and limit the ability of the viral genomic RNA to replicate and/or inhibit virion formation. Although Bitko et al. have not measured viral RNA levels directly, it is very likely that these were also reduced, and treatment with siRNAs even after the acute phase of infection may have a clinical benefit on RSV co-morbidities such as asthma/wheezing later in life.

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By Dirk Haussecker. All rights reserved.

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