An experimentally developed small interfering RNA (siRNA) molecule protects macaques against the otherwise deadly Zaire Ebola virus, according to virologist Thomas Geisbert of the University of Texas Medical Branch in Galveston and formerly from Boston University School of Medicine in Boston, Mass., and his collaborators.
Their effort is one of a growing number to develop siRNA molecules, which bind to specific mRNA molecules, to harness the RNA interference gene silencing mechanism as a way of treating viral infections or other diseases. Thus, in addition to controlling high cholesterol, a variety of cancers, and Huntington's disease, siRNA molecules are being evaluated for their effectiveness against several viruses.
The use of siRNA to control the Ebola virus is particularly interesting because this virus is so deadly-killing, for example, about 90% of humans it infects. The experimental siRNA treatment being tested by Geisbert depend also on use of a delivery system consisting of stable nucleic acid-lipid particles (SNALPs). The particles incorporate siRNA molecules that target the Ebola virus during three different parts of its life cycle, interfering with the mRNA products of three viral genes-encoding L polymerase, viral protein 24, and viral protein 35. "This delivery system could be used for other viral infections," Geisbert says. The SNALP technology itself is under development at Tekmira Pharmaceuticals Corp. in Vancouver, British Columbia, Canada.
To evaluate the effectiveness of this combined siRNA-SNALP approach, healthy macaques were infected with a potentially lethal dose of Zaire Ebola virus and then treated with the tripletargeted siRNA-SNALPs for seven days. All the SNALP-treated macaques survived and were free of Ebola virus within 14 days. Further details appear in the May 29, 2010 Lancet (375:1896-1905).
Other siRNA candidate products are being tested clinically. For instance, ALN-RSV01, made by Alnylam Pharmaceuticals in Cambridge, Mass., targets the mRNA for the nucleocapsid protein of respiratory syncytial virus (RSV), the most common cause of infant hospitalization in the United States. No vaccine is available to protect infants against RSV infections, and the only drug approved for treating such infections (ribavirin) has limited activity.
Because of ethical concerns in testing infants, John DeVincenzo of the University of Tennessee School of Medicine in Memphis and his collaborators are evaluating an experimental siRNA therapy for RSV in adults. The treatment, delivered as a nasal spray, reduces the RSV infection rate, resulting in a 95% increase in infection- free volunteers compared to those treated with a placebo, they report. "The ultimate goal is to create a therapy for children with RSV," he says. Details appear in the May 11, 2010 Proceedings of the National Academy of Sciences (107:8800- 8805).
Although viruses are good targets for siRNA, bacterial pathogens in general are not, according to DeVincenzo. However, he says, genes that regulate host responses to bacterial toxins such as inflammation "have great potential for siRNA therapy."
In yet another development, a topical treatment with two siRNAs disables two key genes necessary for transmitting herpes simplex virus type 2 (HSV-2), and its experimental use protects mice against HSV-2 infections. One siRNA silences the herpesvirus gene UL29, needed for viral replication, and the other knocks out nectin-1, a surface protein located on mouse and human vaginal cells. Neither siRNA delivered alone is sufficient to block HSV. However, when used together, they prevent viral uptake and infection, according to Judy Lieberman at Harvard Medical School in Boston, Mass., and her collaborators. Details appeared in the January 22, 2009 Cell Host and Microbe (5:84- 94).
Despite those promising findings, no companies appear interested in pursuing a partnership to develop this approach to protecting humans against HSV infections, according to Lieberman. "Developing any sort of microbicide does not seem attractive to them," she says. "This is very discouraging, since the public health payoffs could be enormous."
Carol Potera
Carol Potera is a freelance science writer in Great Falls, Mont.
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