Gene silencing seems safe in treating Huntington's disease in adults: study

Treatment strategies that involve turning off a gene responsible for the Huntington's disease in adults appear to be safe, a study using mice said Monday.

The study, published in the U.S. journal Proceedings of the National Academy of Sciences, showed that adult mice don't need huntingtin, the gene that causes the inherited neurodegenerative disorder when mutated in humans.

"The results revealed that deleting huntingtin in the adult brain will not affect brain functions," said Xiao-Jiang Li, who is professor of human genetics at the Emory University School of Medicine.

"Our findings provide an important theoretical basis for effectively treating adult patients with Huntington's disease," said Li, also affiliated with the Institute of Genetics and Developmental Biology at the Chinese Academy of Sciences in Beijing.

Huntington's disease is caused by a gene encoding a toxic protein, or mutant huntingtin, that causes brain cells to die.

Symptoms commonly appear in mid-life and include uncontrolled movements, balance problems, mood swings and cognitive decline.

A juvenile form of Huntington's disease also can appear during the teenage years.

The strategies of lowering huntingtin expression, or gene silencing, are widely believed to be promising in treating Huntington's disease.

In the new study, Li and colleagues used genetically engineered mice in which the huntingtin gene can be deleted, triggered only when the mice are given the drug tamoxifen.

When the huntingtin gene is selectively deleted in the brain at an age older than four months, these mice appeared to stay healthy.

The mice maintained their body weight and could complete tests of movement and grip strength as well as control mice, the researchers said.

Adult mice also had a great reduction in their risk of dying even if they lost their huntingtin genes in cells all over their bodies.

In contrast with adults, engineered mice younger than four months old whose huntingtin gene was deleted developed lethal pancreatitis.

Previously, scientists have already shown that mouse embryos that don't have huntingtin at conception will die in utero, suggesting that the gene is essential for embryonic development.

"When it comes to gene suppression or editing strategies for Huntington's disease, a major concern has been possible side effects because of huntingtin's essential function," said Li.

"Our studies suggest that such concerns may be allayed if deletion of huntingtin occurs only in the adult brain or in older adults."

However, it is possible that other more subtle alterations of behavior or memory are present in the huntingtin-deleted mice, he added.

The researchers noted that additional research could make clear whether the post-natal role of huntingtin tapers off with age in humans in the same way that it does in mice. Enditem