Antisense approaches for inhibiting respiratory syncytial virus

Cramer, H.

doi:10.1517/14712598.5.2.207

Cited by 9 publications

(3 citation statements)

References 105 publications

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“…While a large number of anti-RSV therapeutic strategies have been evaluated, including strategies that use antisense oligonucleotides (12,52,71), deoxyribozymes (79,83,84), small-molecule inhibitors (15,16,55), fusion protein inhibitors (22,26,56), and morpholino compounds (42), no approach has led to any new positive clinical data or FDA-approved products. At the same time, the level of unmet need for safe and effective therapies remains high because of the more than 125,000 pediatric hospitalizations (61) and 170,000 adult hospitalizations (19) in the United States annually.…”

Section: Discussionmentioning

confidence: 99%

RNA Interference-Mediated Silencing of the Respiratory Syncytial Virus Nucleocapsid Defines a Potent Antiviral Strategy

Alvarez

Elbashir

Borland

et al. 2009

Antimicrob Agents Chemother

130

121

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We describe the design and characterization of a potent human respiratory syncytial virus (RSV) nucleocapsid gene-specific small interfering RNA (siRNA), ALN-RSV01. In in vitro RSV plaque assays, ALN-RSV01 showed a 50% inhibitory concentration of 0.7 nM. Sequence analysis of primary isolates of RSV showed that the siRNA target site was absolutely conserved in 89/95 isolates, and ALN-RSV01 demonstrated activity against all isolates, including those with single-mismatch mutations. In vivo, intranasal dosing of ALN-RSV01 in a BALB/c mouse model resulted in potent antiviral efficacy, with 2.5-to 3.0-log-unit reductions in RSV lung concentrations being achieved when ALN-RSV01 was administered prophylactically or therapeutically in both single-dose and multidose regimens. The specificity of ALN-RSV01 was demonstrated in vivo by using mismatch controls; and the absence of an immune stimulatory mechanism was demonstrated by showing that nonspecific siRNAs that induce alpha interferon and tumor necrosis factor alpha lack antiviral efficacy, while a chemically modified form of ALN-RSV01 lacking measurable immunostimulatory capacity retained full activity in vivo. Furthermore, an RNA interference mechanism of action was demonstrated by the capture of the site-specific cleavage product of the RSV mRNA via rapid amplification of cDNA ends both in vitro and in vivo. These studies lay a solid foundation for the further investigation of ALN-RSV01 as a novel therapeutic antiviral agent for clinical use by humans.Human respiratory syncytial virus (RSV) is an ubiquitous virus and the most common cause of serious lower respiratory tract infections in infants and young children worldwide, as well as an important pathogen in elderly individuals and immunocompromised patients (5, 10, 11, 18-21, 62, 64). The worldwide disease burden associated with RSV infection is considerable. RSV is the leading cause of hospitalization for infants (44), with infection rates approaching 70% in the first year of life (25). Approximately 30% of RSV-infected children develop lower respiratory tract infections. RSV results in the hospitalization of approximately 3% of previously healthy infants within their first year of life and a substantially greater percentage of infants and children with underlying diseases (8). RSV is a common cause of childhood bronchiolitis and has been implicated in the development and exacerbation of asthma and reactive airway disease in childhood (39,50,51,54).Despite nearly four decades of research, no RSV vaccine approach has been successful at conferring protection at a level that exceeds the incomplete protection afforded by natural infection. Currently, the only antiviral approved for use for the treatment of RSV infection is ribavirin; but due to its teratogenicity, limited efficacy, and poorly understood mechanism of action, it has very limited use (43,73). Prophylactic therapies include the use of the approved humanized monoclonal antibody palivizumab (Synagis), which targets the fusion protein of RSV (2,27,36). While ...

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Section: Discussionmentioning

confidence: 99%

RNA Interference-Mediated Silencing of the Respiratory Syncytial Virus Nucleocapsid Defines a Potent Antiviral Strategy

Alvarez

Elbashir

Borland

et al. 2009

Antimicrob Agents Chemother

130

121

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“…Of these, only siRNAs have advanced to clinical trials and will be discussed herein. For a thorough review of antisense approaches targeting RSV, see reference[48]. …”

Section: Drug Candidates Targeting Rsvmentioning

confidence: 99%

Pharmacologic Advances in the Treatment and Prevention of Respiratory Syncytial Virus

Empey¹,

Peebles²,

Kolls³

2010

CLIN INFECT DIS

128

107

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There are currently only two drugs approved for respiratory syncytial virus (RSV). Palivizumab is a monoclonal antibody for the prevention of RSV in high-risk children and ribavirin is approved for treatment of severe RSV disease, however its effectiveness in improving outcomes is questionable. Over the past 40 years, many obstacles have delayed the development of safe and effective vaccines and treatment regimens. This article reviews these obstacles and presents the novel development strategies used to overcome many of them. Also discussed are promising new antiviral treatment candidates and their associated mechanism of action, the significant advances made in vaccine development, and exciting, new studies directed at improving outcomes through pharmacologic manipulation of the host response to RSV disease.

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“…Introduction drug, Vitravene, for the treatment of cytomegalovirus (CMV) that caused retinitis in 1998 [13], a large number of antisense compounds have been studied using in vitro and in vivo models and several have been evaluated in human clinical trials [14,15]. For antiviral therapy, many published studies have shown that ASOs can inhibit various viral pathogens such as human immunodeficiency virus (HIV) [16,17], Epstein-Barr virus (EBV) [18], hepatitis B virus (HBV) [19], hepatitis C virus (HCV) [20], respiratory syncytial virus [21,22], and influenza virus [23][24][25] by interactions with essential viral genes [26]. However, ASOs specific for the 5′-terminal conserved sequences of all eight influenza A viral RNAs have not been demonstrated so far.…”

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confidence: 99%

In vitro and in vivo Protection against the Highly Pathogenic H5N1 Influenza virus by an Antisense Phosphorothioate Oligonucleotide

et al. 2008

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Background Current vaccination strategies and antiviral drugs only provide limited protection against influenza virus infection. In this study, we investigated the use of a novel antisense oligonucleotide (named IV-AS), which is specific for the 5’-terminal conserved sequence found in all eight viral RNA segments of influenza A virus. Methods The activity of IV-AS was monitored both in vitro, in Madin-Darby canine kidney (MDCK) cells, and in vivo using a mouse model. IV-AS was given intranasally to H5N1-infected mice once daily for 6 days starting 6 h after infection. A three-base mismatch of IV-AS was used as a control. Results IV-AS inhibited influenza virus A induced cytopathic effects in MDCK cells with the 50% effective concentration (EC50) ranging from 2.2 to 4.4 μM. IV-AS was effective against H5N1 virus in preventing death, lessening weight reduction, inhibiting lung consolidation and reducing lung virus titres. Dosages of 40 and 60 mg/kg/day provided 40% and 60% survival rates and prolonged mean survival days in comparison with the infected control group ( P<0.05). The lung index in mice treated with IV-AS, at a dose of 20, 40 or 60 mg/kg/day, had been inhibited on day 4 or 6 ( P<0.05 or P<0.01); virus titres in lung had declined to 2.42, 1.51 and 1.54 log10 TCID50/g of lung, respectively, whereas the yields in the infected control mice were 6.00 log10 TCID50/g of lung. Conclusions Our results suggest that the 5’-terminal conserved region of influenza A virus RNA segments can be targeted using antisense technology; therefore, IV-AS is a potential drug for prophylaxis and control of influenza virus infections.

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Antisense approaches for inhibiting respiratory syncytial virus

Cited by 9 publications

References 105 publications

RNA Interference-Mediated Silencing of the Respiratory Syncytial Virus Nucleocapsid Defines a Potent Antiviral Strategy

RNA Interference-Mediated Silencing of the Respiratory Syncytial Virus Nucleocapsid Defines a Potent Antiviral Strategy

Pharmacologic Advances in the Treatment and Prevention of Respiratory Syncytial Virus

In vitro and in vivo Protection against the Highly Pathogenic H5N1 Influenza virus by an Antisense Phosphorothioate Oligonucleotide

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