HD is a devastating, inherited, neurodegenerative disease that is progressive and always fatal. The disease-causing gene produces a protein that is toxic to certain brain cells, and the subsequent neuronal damage leads to the movement disorders, psychiatric disturbances and cognitive decline that characterize this disease.
"Many of the current approaches aimed at treating HD are indirect and target the symptoms of the disease. RNA interference gives us the first opportunity to attack the fundamental problem and reduce protein expression from the disease gene," said Beverly L. Davidson, Ph.D., the Roy J. Carver Chair in Internal Medicine and UI professor of internal medicine, physiology and biophysics, and neurology. "Our study is the first demonstration that a therapy designed to inhibit protein production has a beneficial effect."
The study will appear this week in the Online Early Edition of the Proceedings of the National Academy of Sciences (www.pnas). Davidson is the senior author and Scott Harper, Ph.D., a postdoctoral researcher in Davidson's lab, is lead author.
Harper, Davidson and their colleagues used RNAi to treat a mouse model of HD. Viral vectors (stripped-down viruses) carrying the genetic instructions to make a RNA interference molecule were injected into the brains of genetically engineered mice before the disease symptoms appeared. The treated mice showed nearly normal movement, and the characteristic neurological damage also was significantly improved in comparison to untreated mice.
Detailed examination of the protein levels in the treated mice showed that levels of the toxic HD protein were reduced to about 40 percent of the level seen in untreated mice.
"It is very exciting that a partial reduction is sufficient to produce a very beneficial effect in the animal. It means that we don't have to turn the gene off completely," Davidson said. "For a disease that takes decades to develop, a partial reduction may slow down the disease-causing copy of the gene to such an extent that either disease progression is delayed or possibly even disease onset is prevented."
It may even be the case that a partial reduction of toxic protein levels allows the brain cells' machinery to "catch up" with the disease-causing protein and clear out the damage caused by the mutant protein.
The genetically engineered or transgenic mouse model used by the UI team carries a section of the human HD gene. These mice quickly develop movement and coordination abnormalities and they die young. Aggregates, or clumps of protein, also develop in certain brain cells.
Davidson explained that this mouse is very good for proof-of-principle experiments, allowing the researchers to ask a very pointed question “ can RNAi improve HD-like symptoms in a mouse model in short order?
"Since our results are positive, we can now repeat the experiment in mouse models that develop disease more slowly and more closely resemble HD in humans," Davidson said.
Most genes are inherited as a pair, one from either parent. In HD, one mutated copy of the gene is sufficient to cause the disease. However, the normal Huntington gene produces a protein that is known to be critical in embryonic development. It is not known if the protein is critical in adult brain cells.
The RNAi molecule used in Davidson's current study would silence both the mutant and the normal gene. So, an important question that still needs to be addressed is whether adult neurons can tolerate and benefit from a partial reduction of both the toxic and the normal protein. If the normal protein is critical, then RNAi will need to be specifically targeted against the disease-causing gene.
Fortunately, RNAi is exactly the right tool to provide an answer regarding whether the normal gene is critical by silencing the normal gene in adult brain cells of HD models.
Despite the remaining hurdles, Davidson is optimistic about the potential of RNAi to treat HD and similar neurodegenerative diseases.
"If the benefit is confirmed in other mouse models of Huntington's disease, and it appears that we don't need to target the RNAi specifically to the disease-causing mutant gene, then I would think it might move to human testing within several years," she said.
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