A single injection of a novel treatment blocks expression of mutant Huntingtin protein for 6 months in mice
Huntington's disease (HD) is an incurable neurological disorder affecting 1 in every 10,000 people worldwide. Patients diagnosed with adult onset HD rarely lived beyond 15-20 years following diagnosis, and the disease triggers a deadly decline resulting in severe neurological problems, a loss of reasoning capacity and difficulty performing basic tasks such as swallowing and speaking. The disease is caused by a mutation in the Huntingtin gene, leading to an unstable protein with a variable number of CAG repeats in the gene. The length of CAG repeats in an individual reasonably accurately predicts age of onset and severity. Huntington's disease is invariably inherited, with only 10% of cases linked to spontaneous mutation.
Blocking the disease
Scientists at Imperial College London have developed a new method of treatment involving a zinc finger protein. Zinc finger proteins contain a unique domain able to recognise and bind to a specific region of DNA, and are commonly seen in proteins like transcription factors. The London team designed a protein to bind to the mutated form of Huntingtin in a mouse form of the disease - essentially blocking expression of the mutation.
"We don’t know exactly how the mutant Huntingtin gene causes the disease, so the idea is that targeting the gene expression cuts off the problem at its source - preventing it from ever having the potential to act"
The therapy stems from a decade of research into zinc fingers; allowing researchers to carefully optimise the protein and extend its 'blocking' effects for a period of up to 6 months in mice. The scientists tested the therapy by injecting 12 mice once with a dose, and discovered that 77% of mutant gene expression was inhibited in a 3 week period. After 12 weeks 48% remained impaired, and by 24 weeks 23% still remained blocked.
"In this study we weren’t looking at how repressing the gene activity affected the symptoms of the disease, and this is obviously a critical question as well. However, we have reason to be confident from our previous studies that repressing the gene does in fact significantly reduce symptoms"
While the strategy has now been proved in both mice and primates, it's actually not abundantly clear whether preventing expression of the mutant protein is actually a cure for the condition. The mice in the study however did perform much better, but we really need to conduct clinical trials in humans to determine the efficacy, and whether this could be the first real therapy for the disease.
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