"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
Source:University of Iowa