Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque

Li, Bao-jian; Tang, Qingquan; Cheng, Du; Qin, Chuan; Xie, Frank Y; Wei, Qiang; Xu, Jun; Liu, Yijia; Zheng, Bo-jian; Woodle, Martin C; Zhong, Nanshan; Lu, Patrick Y

Development of therapeutic agents for severe acute respiratory syndrome (SARS) viral infection using short interfering RNA (siRNA) inhibitors exemplifies a powerful new means to combat emerging infectious diseases. Potent siRNA inhibitors of SARS coronavirus (SCV) in vitro were further evaluated for efficacy and safety in a rhesus macaque (Macaca mulatta) SARS model using clinically viable delivery while comparing three dosing regimens. Observations of SARS-like symptoms, measurements of SCV RNA presence and lung histopathology and immunohistochemistry consistently showed siRNA-mediated anti-SARS efficacy by either prophylactic or therapeutic regimens. The siRNAs used provided relief from SCV infection–induced fever, diminished SCV viral levels and reduced acute diffuse alveoli damage. The 10–40 mg/kg accumulated dosages of siRNA did not show any sign of siRNA-induced toxicity. These results suggest that a clinical investigation is warranted and illustrate the prospects for siRNA to enable a massive reduction in development time for new targeted therapeutic agents. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nm1280) contains supplementary material, which is available to authorized users.