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Gene silencing improves Huntington's in animals; human tests next

June 22, 2012|By Thomas H. Maugh II
  • Nerve cells in the right side of this dissected brain have been killed by Huntington's disease, creating a large hole.
Nerve cells in the right side of this dissected brain have been killed by… (Harvard Brain Tissue Resource…)

A single injection of an experimental drug designed to silence the gene that produces the mutant huntingtin protein in Huntington's disease can provide long-lasting relief from the condition, studies in rats and monkeys show.

The infusion not only temporarily blocks production of the mutant protein, but also allows the body to clean up some of the huntingtin that has already accumulated, leading to a "huntingtin holiday" that can persist as long as nine months, UC San Diego researchers reported this week. The team hopes to begin human trials of the treatment within 18 months.

Huntington's is a genetic disorder caused by a mutant gene on chromosome 4. The gene produces a protein called huntingtin. Normally, a section of this gene is repeated 15 to 28 times, but in the mutant form, it is repeated as many as 150 times, leading to accumulation of an abnormal form of the huntingtin protein that destroys cells in the brain. The disease produces a broad variety of symptoms, including behavioral disturbances, paranoia, psychosis, movement disorders, dementia and, eventually, death. The disease affects an estimated 30,000 Americans and there is no cure or even an effective treatment.

Researchers have tried a variety of ways to suppress the production of mutant huntingtin. But such suppressive agents have to be injected directly into the brain and they have generally been shown to exert their effects only near the site of the injection.

Cell biologist Don W. Cleveland of UCSD's Ludwig Institute of Cancer Research and his colleagues have developed what is known as antisense DNA that binds to messenger RNA that is the blueprint for the mutant huntingtin protein. Messenger RNA, or mRNA, carries instructions from the cell's nuclear DNA to its protein-making machinery. The antisense DNA is complementary to the huntingtin mRNA and signals cellular enzymes to destroy it. The drug seems to spread through the brain far from the injection site.

The team reported in the journal Neuron that a single injection of the drug into mice with a model of Huntington's disease produced rapid results. Treated animals began moving better within a month and their movements were normal within two months. The improvements lasted as long as nine months, long after the drug has disappeared from their bodies and production of the mutant protein had resumed. Similar results were obtained in rhesus monkeys.

"For a disease 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 prolonged benefit for patients," Cleveland said in a statement. "This finding raises the prospect of a 'huntingtin holiday,' which may allow for disappearance of disease-causing species that might take weeks or months to re-form. If so, then a single application of a drug to reduce expression of a target gene could 'reset the disease clock,' providing a benefit long after huntingtin suppression has ended."

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