New Data Suggests Changes to Existing Huntington's Disease Treatment Approach


Rockefeller University scientists have observed the effects of Huntington’s disease in neurons as early as conception, and suggest therapies that block HTT protein activity may be doing more harm than good.

Scientists at the Rockefeller University in New York have observed the effects of Huntington’s disease (HD) in neurons as early as conception.

Ali Brivanlou, Ph.D. and his team of researchers developed a system in which human embryonic stem cells were used to model the rare disease, and the cells were used to observe embryonic changes in the first stages of development. It was concluded that clinical benefit can be found in early diagnosis and treatment, and the data were published in the clinical journal Development last week.

The neurodegenerative disease is the result of an unbalanced cytosine-adenine-guanine (CAG) repeat expansion in the Huntingtin gene (HTT). The expansion eventually produces a mutant form of the Huntingtin protein, leading to a rapid decline in neuromuscular and cognitive abilities.

In the study, early abnormalities were found in the structure of neurons, as were large masses within cells that had never previously been reported. These findings are noteworthy considering that the disease doesn’t typically present until a patient reaches his or her middle age years. The data could lead to future clinical trials designed to evaluate new approaches and potentially effective therapies for HD patients.

“Our research supports the idea that the first domino is pushed soon after fertilization, and that has consequences down the line. The final domino falls decades after birth, when the symptoms are observable,” said Dr Brivanlou in a statement.

The CRISPR gene-editing technology was used in the engineering of human embryonic stem cell lines identical aside from the number of DNA repeats that occurred at the ends of their HTT genes.

"We started seeing things that were completely unexpected," says Brivanlou. "In cell lines with mutated HTT, we saw giant cells. It looked like a jungle of disorganization. Our work adds to the evidence that there is an unrecognized developmental aspect to the pathology. Huntington's may not be just a neurodegenerative disease, but also a neurodevelopmental disease."

Typically, when cells divide, they each retain one nuclei, however, some of the enlarged mutated cells displayed up to 12 nuclei, proposing that the generation of new neurons (neurogenesis) was effected. The more repeats there were, the more multinucleated neurons appeared, confirming that the disruption was directly proportional to how many repeats were present in the mutation.

While, historically, treatments for HD have mostly been aimed at blocking the activity of the mutant HTT protein, the recent data suggests that the brain disruption could possibly be due to a lack of HTT protein activity. Thus, the researchers created cell lines that completely lacked the HTT protein, which ended up presenting very similarly to those with HD pathology. It was concluded that the idea that a lack of the protein — not an excess of it – is driving the disease.

Before the study, scientists were unsure of the purpose of the HTT gene and could not predict cellular effects of the mutations. The findings are significant in that they led the researchers to believe that existing treatments, therapies that block HTT protein activity, may be doing more harm than good.

"We should rethink our approach to treating Huntington's,” Brivanlou said. "Both the role of the HTT protein and the timing of treatment need to be reconsidered; by the time a patient is displaying symptoms, it may be too late to medicate. We need to go back to the earliest events that trigger the chain reaction that ultimately results in disease so we can focus new therapies on the cause, not the consequences."

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