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
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.
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.
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
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.
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.