Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque.
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.
Li
Bao-jian
BJ
Biotechnology Research Center of Sun Yatsen University, and Key Laboratory of Gene Engineering of Ministry of Education of the State, Guangzhou, China.
Tang
Qingquan
Q
Cheng
Du
D
Qin
Chuan
C
Xie
Frank Y
FY
Wei
Qiang
Q
Xu
Jun
J
Liu
Yijia
Y
Zheng
Bo-jian
BJ
Woodle
Martin C
MC
Zhong
Nanshan
N
Lu
Patrick Y
PY
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016679:Genome, Viral; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000821:virology; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects*; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*
D000998:Antiviral Agents; D034741:RNA, Small Interfering