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Alnylam Pharmaceuticals, Inc. Message Board

  • thirdmeinvestor thirdmeinvestor Jul 10, 2006 1:06 PM Flag

    siRNA vs. Vaccines against Pandemic Flu

    I find the following review article appeared in Trends in Molecular Medicine 1.5 years ago very helpful in understanding the advantage of siRNA over vaccination. For those who are new to the field, the introduction would be useful. This is the first part that is edited slightly.

    "The promise of siRNAs for the treatment of influenza"
    in Trends in Molecular Medicine, Vol. 10, Page 571-4, December 2004,
    by Jack R. Bennink and Tara N. Palmore

    National Institutes of Health, National Institute of Allergy and Infectious Diseases, Laboratory of Viral Diseases, 4 Center Drive, Bethesda, MD 20892, USA

    <Abstract>
    Current WHO reports on the Asian avian influenza virus outbreaks are poignant reminders of the potential for the emergence of highly virulent strains of influenza A virus (IAV) and the fact that it remains a scourge on human health. As IAV drifts and shifts its genetic and antigenic composition, it presents an ever-changing challenge for vaccines and antiviral medications. Short-interfering RNAs (siRNAs) are the latest class of potential antiviral therapeutics to be developed. Recent reports using siRNAs in mice suggest that they hold great promise for the prevention and treatment of IAV infections.

    <Introduction>

    The most effective protection against infection with influenza A virus (IAV) infections is vaccination at this time, but this may change. IAV strains are subtype-classified by their hemagglutinin (HA) and neuraminidase (NA) surface glycoproteins. Inactivated subunit and live-attenuated cold-adapted virus vaccines can be very effective. However, the achievement of peak efficacy, 70�80% among those under 65 and 30�40% among the elderly, is contingent primarily on whether the virus strains included in the vaccine generate an anti-HA antibody response that is capable of effectively neutralizing the circulating strain of the virus.

    The major problem with IAV vaccines is that the virus escapes the neutralizing antibody response by making frequent small changes in the virus HA (antigenic drift). IAV can also reassort its segmented genome when cells are infected with two different virus strains (antigenic shift). For example, human and avian virus genes can mix in a doubly infected cell to generate a reassorted strain possessing the avian HA that might infect and be highly virulent in humans. Antigenic shift and drift are precisely the mechanisms that cause new epidemic and pandemic strains to arise.

    During recent years, investigators have undertaken several new approaches to tackle the antigenic variability of IAV. First, technological advances in molecular virology have enabled the rapid cloning of HA and NA genes from field isolates, as well as their insertion into vaccine strains. Advances in the production of recombinant IAV have represented a major leap forward for the study of IAV, but the application of recombinant technology for vaccines has been limited by the inherent slowness of production, safety testing and government approval. Second, researchers have developed vaccines that target the more conserved internal genes, instead of relying on anti-HA neutralizing antibodies. Heterosubtypic cellular immunity � T-cell immunity that is cross-reactive for different subtypes of IAV � can be targeted to the significantly more conserved internal viral proteins. Although potentially beneficial for reducing mortality and morbidity from new pandemic strains, heterosubtypic immunity is far less effective than neutralizing antibodies for preventing infection and disease and cannot produce �sterilizing� immunity.

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    • An intrinsic limitation of the efficacy of any vaccine is its reliance on the immune status of the recipient. Elderly patients, in particular, frequently fail to mount effective responses following vaccination. Therefore, in addition to vaccination, there are drugs approved for use against IAV. The available drugs have two distinct modes of action. Amatadine and rimantadine block the M2-ion channel, preventing IAV penetration into host cells. Zanamivir and oseltamivir are neuraminidase inhibitors that block the release of IAV particles from sialic acid residues on mucus, serum proteins and cell surfaces. These drugs can prevent IAV infection if provided prophylactically and can reduce the duration of symptoms by one day if given within the first day of illness. Drug activity is not subtype specific, but the usefulness of the ion-channel blockers is restricted by the relatively rapid emergence of drug-resistant variants. Furthermore, expense, potential side effects and the timing of delivery for maximum benefit have limited the use these drugs to high-risk populations.
      The need for novel strategies for the prevention and treatment of IAV infection is evident given the limitations of available anti-IAV strategies. In the United States, an average of 20 000 deaths are annually attributed to IAV, despite the availability of vaccines and drugs. Worldwide, the toll is estimated at up to half a million deaths per year. The greatest danger to humanity would be the emergence of a novel pandemic strain that is not covered by existing vaccines. The past few years have seen emergence of highly pathogenic avian strains that threaten to become transmissible in humans through recombination and mutation in animal hosts.
      siRNA: a promising new approach to anti-influenza therapy
      Ge et al. and Tompkins et al. provide remarkable experimental evidence in mice that short interfering RNAs (siRNAs) might ultimately provide a solution to the variability of the IAV HA. These studies convincingly demonstrate that siRNAs, and the similarly functioning small-hairpin RNAs (shRNAs), expressed by a lentivirus DNA vector can prevent and treat IAV pneumonia in mice. There were reductions in lung virus titers or lethality, or both, using siRNAs specific for conserved regions of the IAV nucleoprotein (NP), acid polymerase (PA) and basic polymerase 1 (PB1), whether administered prior or subsequent to the virus challenge. The results of Tomkins et al. impressively showed protection against a lethal challenge with the highly pathogenic H5N1 and H7N7 IAV strains. Although not yet demonstrated experimentally, a potential advantage over vaccines is that siRNAs might not require an intact immune system.

      • 1 Reply to thirdmeinvestor
      • siRNA: a promising new approach to anti-influenza therapy

        <The what and how of siRNAs>

        siRNAs are 21�25-nucleotide RNAs that act posttranscriptionally to induce homologous sequence-dependent degradation of mRNAs. The native process of sequence-specific silencing involves long double-stranded RNAs (dsRNAs). Long dsRNAs are processed in the cell by the dsRNA-specific endonuclease DICER, which cleaves the targeting dsRNAs into 21�25-nucleotide fragments. The double-stranded siRNAs associate with the RNA-interference silencing ribonucleoprotein complex (RISC). The RISC contains adaptor proteins that bind to the siRNAs and unwind them (helicase activity) to generate single-stranded siRNAs. Another protein in the RISC, Argonaute 2, has RNase or SLICER activity. It cleaves the targeted RNAs (in this case the influenza virus RNA).

        For targeted gene silencing, synthetic short double-stranded siRNAs are transfected into cells. A simplified schematic of siRNA-mediated degradation of influenza virus RNA is shown in
        [[Figure 1. Short-interfering RNA (siRNA)-mediated degradation of influenza polymerase (PA) RNA. To target specific RNAs for degradation, such as influenza PA, complementary synthetic short double-stranded siRNAs are transfected into cells. The double-stranded siRNAs are bound by RNA-interference silencing ribonucleoprotein complexes (RISCs). A helicase protein within the RISCs unwinds the two strands and generates single-stranded siRNAs. The single-stranded antisense siRNAs then bind to complementary influenza PA RNAs and guide SLICER (Argonaute 2) to specifically cleave the influenza PA RNAs at the site of siRNA binding.]].

        The synthetic short double-stranded siRNAs do not require the DICER activity that is necessary for the processing of long dsRNAs. Long dsRNAs are found in virus-infected cells, but generally not in normal eukaryotic cells. The problem with using long dsRNAs is that they activate the interferon (IFN) system and the dsRNA-dependent IFN-inducible protein kinase (PKR). This leads to effects on cytokine signaling and transcription, the degradation of mRNA, the inhibition of translation and cell death. To avoid the adverse effects of long dsRNAs, viruses have evolved dsRNA binding proteins that can inhibit the effects of IFN and antiviral RNA interference. What makes short double-stranded siRNAs more useful for targeted gene silencing is that they induce the homologous sequence-dependent degradation of mRNAs without activating the IFN system. As with the in vivo impact of duplexed siRNAs against IAV observed by Ge et al. and Tompkins et al., the sequence specificity and virus specificity further control for potential IFN induction by dsRNAs and demonstrate that the antiviral effects are not due to IFN.
        siRNAs have been touted as a panacea for a wide range of applications. They have become standard in vitro laboratory tools to block specific gene activity, through the degradation of mRNAs, to inhibit virus replication. Recent reviews emphasize that the use of siRNAs holds great promise not only for combating viruses and other human pathogens but also allergies, tumors, pain and neurological diseases.

 
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