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

Nature Medicine volume 11, pages 944–951 (2005)Cite this article

Abstract

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.

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Figure 1: Selection and validation of siRNA duplexes targeting SCV sequence.
Figure 2: Severity of lung histopathology in SCV-challenged macaques.
Figure 3: Histopathological characteristics of SCV-infected macaque lungs.
Figure 4: siSC2-5 relieved SARS symptoms.
Figure 5: siSC2-5 inhibits SCV replication.

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Acknowledgements

This study was supported in part by the Science and Technology Commission, Guangdong Provincial Government, Guangzhou Science and Technology Bureau, Guangzhou Economic & Technological Development District, and China World Trade Corporation (Guangzhou), Top Biotech, Ltd. (Hong Kong), China. We thank C. Lu, X.S. Zhang and D.C. Zheng of Top Genomics, Ltd. (Guangzhou) for their administrative work to coordinate and facilitate the study; H. Gao, X.M. Tu, L.L. Bao, W. Deng and B.L. Zhang of Institute of Laboratory Animal Science and L. Ruan of Institute of Virology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, for their supports during the study; W. Tian and E. Lader of Qiagen for their collaborative efforts; Y.Y. Gu of Guangzhou Institute of Respiratory Diseases for her advice on lung pathological analysis; and ONY Inc. Amherst, New York, USA for providing Infasurf.

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Author notes

  1. Bao-jian Li, Qingquan Tang, Du Cheng and Chuan Qin: These authors contributed equally to this work.

Authors and Affiliations

  1. Biotechnology Research Center of Sun Yatsen University, and Key Laboratory of Gene Engineering of Ministry of Education of the State, Guangzhou, China

    Bao-jian Li

  2. Guangzhou Top Genomics, Ltd., Guangzhou, China

    Bao-jian Li, Du Cheng & Frank Y Xie

  3. Intradigm Corporation, 12115 K Parklawn Drive, Rockville, 20852, Maryland, USA

    Qingquan Tang, Frank Y Xie, Jun Xu, Yijia Liu, Martin C Woodle & Patrick Y Lu

  4. Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

    Chuan Qin & Qiang Wei

  5. Department of Pathology, University of Hong Kong, Hong Kong, China

    Bo-jian Zheng

  6. Guangzhou Institute of Respiratory Diseases, Guangzhou, China

    Nanshan Zhong

Authors
  1. Bao-jian Li
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Corresponding authors

Correspondence to Nanshan Zhong or Patrick Y Lu.

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Competing interests

Bao-jian Li and Frank Y Xie are consultants for and Du Cheng is an employee of Guangzhou Top Genomics, Ltd. Qingquan Tang, Frank Y. Xie, Yijia Liu, Martin C. Woodle and Patrick Y. Liu are employees of Intradigm Corporation. Both Top Genomics, Ltd. and Intradigm Corporation are biopharmaceutical companies that are developing RNAi therapeutics for the treatment of human disease.

Supplementary information

Supplementary Fig. 1

siSC2-5 protect cells from CPE after SCV infection. (PDF 105 kb)

Supplementary Fig. 2

SCV RNA detection in lung tissues. (PDF 187 kb)

Supplementary Table 1

Blood biochemistry tests. (PDF 80 kb)

Supplementary Table 2

Routine blood tests. (PDF 76 kb)

Supplementary Table 3

Internal organ coefficient of tested animals. (PDF 68 kb)

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Li, Bj., Tang, Q., Cheng, D. et al. Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque. Nat Med 11, 944–951 (2005). https://doi.org/10.1038/nm1280

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