Treatments that target a fragment of the mutant protein that causes Huntington's disease might be more effective than treatments, now in clinical trials, that target the whole protein but leave this fragment intact, a new study in mice suggests.
"I hope we're wrong, but the science behind our findings is solid," said senior author Jeffrey Carroll, an associate professor of neurology at the University of Washington School of Medicine in Seattle. "To succeed, we may need to design new treatments that also target this specific region of the protein."
The findings appear March 18 in Science Translational Medicine.
Huntington's is caused by a mutation in a gene called huntingtin. The mutation produces an abnormal protein that accumulates in brain cells. There it interferes with a wide range of cellular functions, and forms large aggregates of the protein that lead to cell death. A person needs to inherit only one parent's copy of the mutant gene to acquire the disease.
People with Huntington's typically begin experiencing symptoms in their 40s, although onset can be earlier or later. Early symptoms include uncontrolled movements, called Huntington's chorea, clumsiness and balance problems. As the disease worsens, a person with Huntington's will lose the ability to walk, talk and swallow, and eventually require 24-hour care. Personality changes and dementia are common with advanced disease. The condition progresses inexorably and is fatal within 10 to 15 years after symptoms appear. About 41,000 Americans have Huntington's and more than 200,000 are at risk of developing the disease.
Currently no effective treatment exists, but several experimental therapies are being tested. The most promising approach prevents the production of the abnormal protein by sabotaging the process by which the DNA instructions encoded in the gene are translated into protein.
In this process, the gene's DNA instructions are first copied into a form of RNA, called messenger RNA (mRNA), which the cell then reads to assemble the protein. Researchers can disrupt this process by introducing a short sequence of DNA, called an antisense oligonucleotide, that binds to a specific site on the mRNA strand. This causes enzymes in the cell to cut the strand at that site, thereby preventing the cell from producing the complete protein. The cleaved mRNA and incomplete protein are then eliminated by the cell.
In their new study, Carroll and his colleagues initially wanted to compare antisense oligonucleotide treatments that reduced the production of all huntingtin proteins — both the normal and mutant versions — with a treatment that blocks production only of the mutant version.
As it turned out, the treatment that worked best with the type of mouse they were studying bound to the mRNA very near the beginning of the strand. This meant it not only suppressed the production of the whole protein but also suppressed the production of a very short segment of the protein called huntingtin 1a. Huntingtin 1a is known to be toxic to nerve cells, but its role in Huntington's disease is not well understood.
After the researchers treated mice that had one copy of the aberrant gene, they assessed the effectiveness of the treatments by looking at the expression of more than 150 genes that are affected in Huntington's disease. They also checked for the protein aggregates that are a hallmark of the disease.
Treatment that blocked production of the whole protein, but not huntingtin 1a, made little difference. But treatment with the antisense oligonucleotide that prevented production of huntingtin 1a appeared to be remarkably effective. For example, the expression of about 55% of the genes normally affected in Huntington's disease went back to baseline, and the formation of aggregates was almost eliminated.
"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," said Robert Bragg , the study's first author and a research scientist in the Carroll laboratory. "I had to look really hard to even find one or two."
"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," Bragg said. "It looks like you really need to lower huntingtin 1a to be effective."
Written by Michael B. McCarthy.
