title: Application of siRNA against SARS in the rhesus macaque model.
abstract: Containment of the SARS coronavirus (SCV) outbreak was accompanied by the rapid characterization of this new pathogen's genome sequence in 2003, encouraging the development of anti-SCV therapeutics using short interfering RNA (siRNA) inhibitors. A pair of siRNA duplexes identified as potent SCV inhibitors in vitro was evaluated for in vivo efficacy and safety in a rhesus macaque SARS model using intranasal administration with clinical viable delivery carrier in three dosing regimens. Observations of SCV-induced SARS-like symptoms, measurements of SCV RNA presence in the respiratory tract, microscopic inspections of lung histopathology, and immunohistochemistry sections from 21 tested macaques consistently demonstrated siRNA-mediated anti-SCV activity. The prophylactic and therapeutic efficacies resulted in relief of animals from SCV infection-induced fever, diminished SCV in upper airway and lung alveoli, and milder acute diffuse alveoli damage (DAD). The dosages of siRNA used, 10 to 40 mg/kg, did not show any sign of siRNA-induced toxicity. These results support that a clinical investigation of this anti-SARS siRNA therapeutic agent is warranted. The study also illustrates the capability of siRNA to enable a massive reduction in development time for novel targeted therapeutic agents. We detail a representative example of large-mammal siRNA use.
authors: OriGene Technologies Inc, Rockville, MD, USA.
authors: Qingquan
authors: Q
authors: Tang
authors: Baojian
authors: B
authors: Li
authors: Martin
authors: M
authors: Woodle
authors: Patrick Y
authors: PY
authors: Lu
mesh_terms: D000818:Animals; D001483:Base Sequence; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D006801:Humans; D008168:Lung / Q000166:cytology / Q000473:pathology / Q000821:virology; D008253:Macaca mulatta; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D045473:Severe acute respiratory syndrome-related coronavirus / Q000235:genetics* / Q000378:metabolism; D045169:Severe Acute Respiratory Syndrome / Q000517:prevention & control* / Q000628:therapy* / Q000821:virology
chemical_list: D034741:RNA, Small Interfering