Gene Therapy Safety (08.22.03) Stop That Gene (07.08.03) Centers for Disease Control and Prevention The RNAi Information Portal A new type of drug can disable dangerous viruses by switching off specific genes. As this ScienCentral News video explains, the federal government is backing efforts to develop these drugs against an influenza pandemic or a bioterror attack. Anti-Genes It was only a few years ago that researchers at Stanford University led by Mark Kay showed they could stop viruses in mice by designing tiny pieces of the genetic material RNA to specifically match key virus genes and turn them off. The technique, called RNA interference, uses our cells' own machinery to silence genes. "The use of this new technology called RNA interference can be thought about from the standpoint of being a anti-gene," says Kay. "That is, a method of delivering something that can actually shut down viral genes and stop them from functioning." Video courtesy Nature Reviews Genetics and Arkitek Studios The problem, Kay says, is "historically with gene therapy you have a hard time getting enough into cells." When his team found a way to boost the dose, they discovered that too much is toxic. Kay says they've eliminated the toxicity by backing off the dose by controlling how much of the RNA-coding gene gets expressed in cells. "We now have vectors with a wide and safe therapeutic window," he says. Meanwhile, other researchers are pursuing ways to administer RNAi therapies without using gene therapy. "The main challenge for creating new medicines based on RNA interference technology has been how do you get these drugs into the body so they can work," says Alnylam Pharmaceuticals CEO John Maraganore . The first RNAi therapies to make it to human clinical trials administer the small RNA's directly and repeatedly into diseased cells. RNAi drugs being investigated by Sirna and Acuity Pharmaceuticals for age-related macular degeneration (AMD) are injected into the eye, while Alnylam's investigational drug against a viral type of pneumonia is delivered to the lungs using nebulizer treatments. Vaishnaw says that's long enough for it to be promising for combating emergency threats like pandemic influenza or bioterror agents like Ebola . "For many infectious diseases where you're talking about short-term treatment, length of administration is not a problem," he says. The company has won support from the Department of Defense to develop drugs against pandemic flu. And it's being funded by the National Institute of Allergy and Infectious Diseases (NIAID) to develop drugs against potential bioterror viruses. Kay points out that both methods still have safety issues to be worked out, because our cells use RNAi themselves for regulating genes. He says this brings a paradox: " The advantage to using RNAi is that the machinery is in our cells -- while the disadvantage of RNAi is that the machinery is in our cells. " But he adds that this new type of medicine must first be proven to be safe and effective in people who are already sick. "It has great potential, but it will take time to get it to work and make a difference in even good model diseases," he says. The researchers recently presented their findings at the 2007 meeting of the American Association for the Advancement of Science in San Francisco. Kay's research was published in Nature , May 25, 2006 and Nature Biotechnology , June 2003 and funded by the National Institutes of Health (NIH) and the Anna Ng Charitable Foundation. Alnylam Pharmaceuticals has research published in Nature , March 2006; Nature Medicine , December 26, 2004 (AOP); and Nature , November 11, 2004 and has funding from the Department of Defense (DoD) and National Institute on Allergy and Infectious Diseases (NIAID/NIH).