Pardridges results look pretty encouraging, says Rossi, but there are a lot of ifs. One problem is that liposomes are mildly toxic, which could hold back their use in humans; another is the design of the study itself, which leaves open the possibility that the survival benefit resulted from a general immune reaction to the liposomes or the RNA moleculesnot from a specific RNAi mechanism. While Rossi believe the technology has a chance of working in humans, Pardridge is convinced; he plans to develop the liposomes for use in humans through ArmaGen Technologies, a company he founded in Santa Monica, CA, to commercialize gene delivery technologies. By varying the antibodies on the surface, Pardridge says, liposomes could be targeted to any tissue in the body.
In the second study, Beverly Davidson, associate director of the Iowa Center for Gene Therapy, has used a combination of gene therapy and RNAi to treat a mouse model of an inherited nerve-destroying disease related to Huntingtons. In research presented June 4 at the 2004 meeting of the American Society for Gene Therapy, Davidson employed a disabled virus to deliver RNAi-based gene therapy that blocked production of a mutant protein in the brains of mice affected by the disease, known as spinocerebella ataxia type 1 (or SCA1). Unlike many genetic diseases in which gene therapy can add back a normal version of a mutated protein, so-called dominant genetic illnesses, such as SCA1 and Huntingtons, have not been able to benefit from gene therapy because the mutant protein causes symptoms even if a normal copy of the protein is present. This is the first shot at getting at these dominant genetic diseases, says Davidson, who hopes to have the technique ready to test in humans within five years. Huntingtons will be the likely first target, she says.
Despite the encouraging results from these three studies, drug companies would ideally like to be able to use RNAi as a drug without any extras that would complicate manufacturing. Following stunning early successes, several startups were launched to develop RNAi into drugs. Several of the companies are working on a direct approach to the delivery problem: chemically modifying the RNA molecules to stabilize them in the blood and also to get them taken up into cells and tissue. A lot of it hasnt been published yet, but it certainly will be coming out soon, says Rossi, who cites therapeutic companies Sequitur (now part of Invitrogen), Atugen, Sirna, and Alynylam Pharmaceuticals as leaders in this area. Drug companies would like to have the simplest formulation possible, he adds. Using RNA molecules directly, he says, would be the ultimate goal.
Success is far from assured. Gene therapists have been trying to deliver naked DNA into cells for well over 25 years, with very limited success, says Mark Kay, director of the Program in Human Gene Therapy at Stanford University School of Medicine, who is investigating RNAi for the treatment of hepatitis. And DNA is a more stable molecule than RNA. Its hard to know which delivery methods will win out, Kay says. But, he adds, If I had to bet right now, I think I would bet on gene therapy techniques such as Davidsons, using viruses to deliver the therapeutic molecules.
Chances are, different methods will end up being used to treat different diseases. And regardless of the final winners, the new results offer concrete hope that biologists may finally be inching closer to delivering on the promise of RNAi.