A new study in mice suggests that treatments targeting a specific fragment of the mutant protein responsible for Huntington's disease could be more effective than current therapies that target the whole protein but leave this fragment intact. The findings were published on March 18 in Science Translational Medicine.
The research is significant because it points to a possible reason why some experimental therapies have not been as successful as hoped. Huntington's disease is caused by a mutation in the huntingtin gene, which leads to an abnormal protein accumulating in brain cells and causing cell death. About 41,000 Americans are affected by the disease, with more than 200,000 at risk.
Jeffrey Carroll, senior author and associate professor of neurology at the University of Washington School of Medicine, said, "I hope we're wrong, but the science behind our findings is solid. To succeed, we may need to design new treatments that also target this specific region of the protein."
Current experimental therapies often use antisense oligonucleotides to disrupt production of the abnormal huntingtin protein by binding to messenger RNA (mRNA) and preventing full protein synthesis. In their study, Carroll and his team compared different antisense oligonucleotide treatments in mice carrying one copy of the mutant gene. They found that only treatments suppressing both the whole protein and a short segment called huntingtin 1a—known to be toxic to nerve cells—were effective.
Robert Bragg, first author and research scientist in Carroll's laboratory, described his surprise at the results: "When I looked at the cells of the treated mice under the microscope, I thought I had made a mistake because at first I could find no protein aggregates. I had to look really hard to even find one or two." Bragg added, "It appears that if you lower the expression of the full Huntington's protein, but huntingtin 1a is still being expressed, it doesn't move the needle at all. It looks like you really need to lower huntingtin 1a to be effective."
The study indicates that future treatment strategies for Huntington's disease may need to focus specifically on reducing levels of huntingtin 1a for better outcomes.
