2-5A antisense treatment of respiratory syncytial virus

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Although a prominent cause of upper and lower respiratory tract disease in infants and the elderly, clinical options for treatment of respiratory syncytial virus (RSV) infections remain limited. Historically, attempts to develop vaccines have been unsuccessful, and rapid viral mutation rates have stifled development of several small molecule-based antiviral agents. Thus, targeted approaches to block RSV replication, including humanized monoclonal antibodies and nucleic acid-based strategies (antisense and RNA interference), have emerged as potentially viable drug development options.

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Introduction: respiratory syncytial virus

Respiratory syncytial virus (RSV) is a non-segmented negative-strand RNA virus that is a major cause of lower respiratory tract disease in infants, young children and the elderly, particularly those that are institutionalized [1, 2, 3]. Outbreaks in the US frequently reach epidemic proportions during the winter months, accounting for approximately 90 000 hospitalizations and more than 500 deaths per year [4], with some estimates ranging as high as 4000 [5] to 17 000 [6] deaths annually. RSV

Viral replication

RSV belongs to the Paramyxoviridae family of RNA viruses, and is further classified to the Pneumoviridae subfamily [12]. RSV replicates within the cytoplasm of epithelial cells lining the respiratory tract, where it causes severe damage, often promoting formation of the fused multinucleated giant cells (syncytia) that gave rise to its name. The 15.2 Kb RNA genome is a single-stranded negative-sense RNA molecule that encodes the structural and non-structural genes illustrated in Figure 1a.

Current treatment and prophylactic agents for RSV

As RSV infections do not induce long-term complete immunity, patients are usually re-infected throughout life. Prior infection can augment severity of subsequent natural disease and lead to increased risk of asthma and wheezing later in life [15], a feature that has hampered efforts to develop vaccines against RSV. Early work with formalin-inactivated viral vaccines was disastrous, with immunized children exhibiting exacerbated disease upon infection despite the presence of neutralizing

Challenges to developing effective RSV therapeutics

Clearly, there remains a strong need for new and effective anti-RSV treatments, prophylactics or vaccines. Beyond the restrictions described already (e.g. infection at a young age, incomplete immunity), the development of therapeutics is hampered by the relatively short treatment window and the fact that RSV, as with most other respiratory viruses, mutates frequently and replicates entirely within the cell (unlike bacterial or mycotic pathogens). Because symptoms associated with many

Oligonucleotide compounds as drug candidates and as RSV therapeutics

Antisense oligodeoxyribonucleotides (ODNs) are short (18–25 nucleotide) single-stranded molecules that are frequently (but not exclusively) designed to inhibit RNA expression or function by annealing to complementary regions of the targeted mRNA by Watson–Crick base pairing. The newly formed RNA:DNA hybrid attracts endogenous ribonuclease H (RNase H) that cleaves the RNA portion of the hybrid [22]. This leads to transcript degradation and/or prevents translation into proteins. As unmodified

The 2-5A antisense strategy

Interferons (IFNs) are synthesized and secreted by cells following exposure to virus. Once secreted, IFNs act upon neighboring cells to inhibit the replication of many different DNA and RNA viruses [35]. They increase the abundance of specific effector proteins encoded by early response genes known collectively as IFN-stimulated genes, which mediate the physiological effects associated with IFNs [36]. Included among the hundreds of IFN-regulated proteins identified to date are the 2-5A

2-5A antisense inhibition of RSV

To date, five papers have described the use of 2–5A antisense strategies to target RSV [44, 45, 46, 47, 48]. The earliest approach used 2-5A antisense chimeras directed against RSV mRNAs [44]. This strategy was moderately efficacious in a cell culture system, but a subsequent study demonstrated that enhanced activity could be achieved by instead targeting conserved intergenic elements found interspersed within the viral genome [45]. This 2-5A anti-RSV approach was similar to that taken by

Conclusions and future directions

Although the studies summarized here suggest that RBI034 and its variants are highly effective in vitro and in vivo, it must be recognized that the 2-5A anti-RSV strategy is not without drawbacks. Synthesis of 2-5A antisense chimeras is technically challenging, and the cost of current raw ingredients, coupled with the need for further procedural development for production scale-up, has hampered inception of additional primate studies or clinical trials in humans. It is uncertain whether the

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

I would like to thank Drs Hagen Cramer, Paul Torrence and Robert Silverman for strong scientific collaborative ties and valuable technical discussions relevant to the topic discussed herein. Supported in part by National Institutes of Health grants CA90837 and CA92979 (to DWL).

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