Huntington's disease gene-silencing drug effective in animal studies

A single dose of an 'antisense' drug has been shown to slow, or even partially reverse, Huntington's disease in animal studies, according to a study published in Neuron.

Huntington's disease is caused by a mutation of the huntingtin gene, which produces fragments of toxic protein that build up in the brain. The build-up eventually leads to characteristic uncontrolled movements, as well as cognitive and psychiatric problems. There is currently no effective treatment available.

The potential new therapy is based on single strands of DNA called 'antisense oligonucleotides' (ASOs). The ASOs selectively attach themselves to messenger molecules sent by the defective gene and destroy them, blocking the signal that produces the mutant protein.

In tests, mice showed significant improvements in both behavioural and physical symptoms after an injection of ASOs, even in those with an advanced form of the disease. After one month of treatment, the mice showed a significant improvement in motor function, and after two months they were approaching normal levels of movement.

The improvements persisted for up to nine months after treatment, even after levels of the toxic protein fragments had built up again. In severe cases of the disease, the ASOs appeared to prolong lifespan and dramatically slow brain cell death.

The study was carried out at the Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine at the University of California, in collaboration with Genzyme, Isis Pharmaceuticals and the Novartis Institutes for BioMedical Research.

Symptoms of Huntington's disease usually begin to appear between the ages of 30 and 50 in people with the defective gene, but the mutant protein can build up for years before manifesting itself. A genetic test can detect the presence of the mutation long before the disease takes hold, and so the possibility of slowing the production of the protein before it causes real damage could one day become a reality.

'Our approach is feasible for development now into a therapy for Huntington's disease in man', said lead author Professor Don Cleveland, from the University of California at San Diego. 'For diseases like Huntington's, where a mutant protein product is tolerated for decades prior to disease onset, these findings open up the provocative possibility that transient treatment can lead to a prolonged benefit to patients'.

Most potential treatments have looked into alleviating the symptoms of Huntington's disease rather than reversing the damage, as multiple areas of the brain are affected, making them difficult to target.

Professor Cleveland said that the ASO approach is especially promising because antisense therapies have already been approved in clinical trials, and researchers are looking into other potential applications. He said the findings may have implications for other 'age-dependent neurodegenerative diseases that develop from exposure to a mutant protein product' and perhaps for nervous system cancers, such as glioblastomas.