Qingquan Tang

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.

Inhibition of Ocular Angiogenesis by siRNA Targeting Vascular Endothelial Growth Factor Pathway Genes : Therapeutic Strategy for Herpetic Stromal Keratitis

Ocular neovascularization often results in vision impairment. Frequently vascular endothelial cell growth factors (VEGFs) are mainly responsible for the pathological neovascularization as in the case in neovascularization induced by CpG oligodeoxynucleotides and herpes simplex virus infection in this report. siRNAs targeting either VEGFA, VEGFR1, VEGFR2, or a mix of the three were shown to significantly inhibit neovascularization induced by CpG when given locally or systemically. The efficacy of systemic administration was facilitated by the use of a polymer delivery vehicle. Additional experiments showed a significant inhibitory effect of the siRNAs mix when given either locally or systemically in vehicle against herpes simplex virus-induced angiogenesis as well as against lesions of stromal keratitis. These results indicate that the use of VEGF pathway-specific siRNAs represents a useful therapy against neovascularization-related eye diseases.

Application of siRNA Against SARS in the Rhesus Macaque Model

Summary Containment of the SARS coronavirus (SCV) outbreak was accompanied by the rapid characterization of this new pathogens 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.