Antisense oligonucleotides directed against the viral RNA polymerase gene enhance survival of mice infected with influenza A

Abstract

We have investigated the ability of antisense phosphorothioate oligonucleotides to enhance the survival of mice infected with influenza A virus. The oligonucleotides were complementary to sequences surrounding the translation initiation codons of the viral PB2 or PA genes (PB2-as or PA-as, respectively) of the influenza A virus RNA polymerases. Intravenous administration of PB2-as in a complex with a cationic liposome, Tfx-10, significantly prolonged the mean survival time in days and increased overall survival rates of mice infected with the influenza A virus. Liposomally encapsulated PB2-as inhibited viral growth in lung tissues and reduced pulmonary consolidations. Liposomally encapsulated PB2-as could be an effective therapeutic agent against influenza A virus.

Inhibition of Multiple Subtypes of Influenza A Virus in Cell Cultures with Morpholino Oligomers

“…DNAzymes (46), oligoaptamers (45), and short interfering RNA (10,12) have all been documented to have antiviral activity in cell culture, and short interfering RNA has been documented to have antiviral activity in mice (11,47), against FLUAV. Intravenous delivery in mice of a liposome-encapsulated antisense phosphorothioate oligonucleotide with sequence complementary to the translation start site region of PB2 mRNA reduced FLUAV titers in lung tissue and significantly increased overall survival rates (26,27). To ultimately achieve clinical utility, any nucleic acid-based anti-FLUAV therapeutic will need to possess a number of favorable pharmacologic qualities, including in vivo stability, low toxicity, and the ability to reach viral RNA targets within relevant cell populations.…”

A phosphorothioate antisense oligodeoxynucleotide specifically inhibits coxsackievirus B3 replication in cardiomyocytes and mouse hearts

“…12 Because of the small and simple nature of the viral genome as compared to other organisms, AS-ODN antiviral strategies have great potential to achieve specific inhibition. In the past years, the antiviral effects of AS-ODNs have been demonstrated in a number of different viruses such as influenza A virus, 13 human immunodeficiency virus, 14 hepatitis B virus [15][16][17] and foot-andmouth disease virus. 18 However, the effectiveness of unmodified AS-ODNs is limited by the low efficiency of cellular uptake and the lack of stability due to degradation by nucleases.…”

Reduction of liver tumor necrosis factor‐α expression by targeting delivery of antisense oligonucleotides into Kupffer cells protects rats from fulminant hepatitis

“…There are advantages to using ASOs to therapeutically suppress gene expression for short periods of time [15]. The main obstacle to the application of ASOs for therapy is the delivery of ASOs to the right tissues and cells in vivo [17][18][19][20].…”

“…In addition to being widely used in tissue culture to inhibit gene expression, antisense oligonucleotide technology also has been applied to reduce target gene expression in animals or human beings and has demonstrated pharmacological activity in vivo [13][14][15][16][17]. Recently, Yoshizumi et al [18] successfully applied antisense nucleotide against TNF-α in the treatment of the injury of the hepatic graft in liver transplantation.…”