Before SPC3649's potential as an HCV drug can be tested in humans, Orum's team has to address its safety. The current phase I trial testing four different doses of SPC3649 in healthy, HCV-negative patients should shed light on this question when it is finished in the first half of 2010. Because miR-122 normally regulates cholesterol levels, the most likely side effect would be upsetting the levels of cholesterol particles—both the "good" (HDL) and "bad" (LDL) varieties. In chimpanzees SPC3649 reduced cholesterol levels by about 40 percent, which Orum says did not affect their health and is similar to the effect of cholesterol-lowering drugs, namely statins. In general, he does not expect that inhibiting a microRNA would completely upset a cellular process. "MicroRNAs do not act as on/off switches; they act as fine tuners of physiological pathways," he says.
If SPC3649 helps to eradicate HCV in humans, clinicians would have reduced fear of the virus developing resistance. To do so, a virus would have to emerge that has acquired a different mode of replication, which would likely involve multiple mutations. If the virus were able to adapt to replicate without miR-122, "we would have very likely have picked up mutations during the [period of miR-122] suppression that would have repopulated the chimps," Orum says. "With direct-acting drugs [such as protease inhibitors], you pick up escape mutants with days of treatment."
The search for a vaccine
Groups working to develop a vaccine against HCV have several obstacles to contend with. "Basically we're facing the same issues as people trying to develop an HIV vaccine," NIDDK's Liang says. These groups face "all the same problems," adds Liang, who is trying to show the effectiveness—first in chimpanzees—of his own vaccine candidate.
These problems are threefold, as Liang explains: The first is that the envelope proteins that coat the virus's outer membrane do a poor job of stimulating an antibody response in the host. This poor immunogenicity is probably part of the reason, Liang says, that HCV is the only RNA virus (though HIV has an RNA genome, it is considered a retrovirus) that is able to persist in the host and cause chronic infection. Secondly, any vaccine would have to protect against the mix of viral species in a patient, by finding a region of envelope proteins that is important enough to be conserved between the different species. Lastly, the virus has evolved strategies to evade the immune response, for example, by repressing the host's interferon response
Still, several vaccine candidates are in clinical testing, albeit in early, safety trials. Liang says that it will probably be possible to eventually find regions of envelope proteins that are conserved between different species. Another question will be how to deliver them to the host. Although some groups, like the vaccine development team at Novartis Pharmaceuticals, are testing these protein fragments in solution, Liang and his colleagues are trying to assemble them in "viruslike particles." "We think that viruslike particles mimic the virus much better than soluble proteins," Liang says.