MINNEAPOLIS--For the first time, researchers have used small RNA molecules packed into viruses to treat mice with an inherited disease. The achievement improves the odds that RNA interference (RNAi) will reach human clinical trials.
Huntington's disease and spinocerebellar ataxia (SCA) are inherited diseases in which nerves degenerate and cause loss of coordination and spasticity. Both diseases stem from a defective protein. Removing the toxic protein is a tricky task, one that current drugs can't tackle. RNAi is a new candidate, because it derails the specific messenger RNA (mRNA) that help manufacture the defective protein.
To test the approach, Beverly Davidson of the University of Iowa in Iowa City and colleagues built a virus that, after infecting a cell, produces short hairpin RNA corresponding to defective ataxin-1, the cause of SCA. Similar efforts are under way with Huntington's, but the mRNA for ataxin-1 is shorter and easy to work with, Davidson says. The researchers injected the virus into the brains of diseased mice that carry the human version of SCA. Normally, these mice suffer from the degeneration of Purkinje cells in the cerebellum, a part of the brain important for balance and movement. But mice treated with the RNAi virus showed signs of improvement; they kept their balance on a rotating rod longer than untreated diseased mice (but not as long as healthy mice), Davidson reported here on 4 and 5 June at a meeting of the American Society of Gene Therapy.
Mark Kay, a geneticist at Stanford University in California whose lab has used RNAi to treat hepatitis B in mice (ScienceNOW, 12 May 2003), calls Davidson's research "extremely well done and extremely promising." The success of animal tests is a "major" advance, adds Donald Kohn, an immunologist at Children's Hospital of Los Angeles. However, he cautions that there is still "a major scientific gulf to bridge between this proof in a mouse and taking it to humans." Safety trials of an RNAi-based therapy in people could start in the next few years, Kay says.