SAHA Treats HD Mice

HD Lighthouse Contributing Editor's Comment: Good news. --Jerry
Posted to the HDL: 04 Feb 2003

Dramatic Improvement
The drug is called SAHA (suberoylanilide hydroxamic acid) and the researchers "found that it dramatically improved movement impairment in a mouse model of Huntington's disease," said Dr. Gillian P. Bates of King's College London, UK.

NEW YORK (Reuters Health) - An experimental drug appears to delay symptoms in mice with a condition similar to the degenerative brain disorder Huntington's disease, scientists announced on Monday.

Such mice, which are genetically modified to develop symptoms similar to those of Huntington's in humans, "are the closest models that we have to the human disease," added Bates.

SAHA is in a class of drugs known as histone deacetylase (HDAC) inhibitors, according to the report in the February 3rd issue of the journal Proceedings of the National Academy of Sciences (news - web sites). Such inhibitors are aimed at the root cause of Huntington's disease--the transcription of DNA into working proteins.

Huntington's disease is a genetic disorder afflicting about 35,000 to 50,000 people in the United States. The disease is characterized by the death of brain cells, usually starting in middle age, leading to involuntary jerky movements, personality changes and mental deterioration. It is inherited through a mutated gene that produces an abnormally long version of a protein.

One effect of the faulty gene, explained Bates, is that it alters the extent to which other genes important for the function of brain cells are switched on. In most cases, the level at which these genes are switched on has been turned down.

"It could be compared to a rail network in which certain trains start to run at a reduced speed. The function of the whole network becomes affected," Bates told Reuters Health.

The precise molecular interactions that lead to genes being turned down is not yet understood, although many clues are emerging from research, according to Bates.

So far, HDAC inhibitors have shown promise when used to treat laboratory-grown cells and fruit flies that share some of the same DNA transcription problems associated with Huntington's disease.

In the new study, the drug was administered in water and appeared to readily cross the blood-brain barrier, which shields the brain from contact with body substances.

Typically, the genetically engineered mice develop severe movement problems at five to six weeks of age. Those treated with SAHA for three weeks had a delay in symptoms compared with mice given a placebo.

At 12 weeks of age, the treated mice performed as well as untreated mice at eight weeks of age. The drug did appear to be somewhat toxic, and mice did not gain weight at the same rate as placebo-treated mice.

"It is extremely exciting that one of these drugs is effective in the mice and this has provided the green light to further develop HDAC inhibitors for use in the clinic to treat Huntington's disease (in people)," said Bates.

However, much more study is needed to determine if such drugs are safe and effective for humans.

"Our research into HDAC inhibitors will continue on two fronts," noted Bates. "First, we aim to develop effective HDAC inhibitors that could eventually be used in the clinic as treatments for Huntington's disease and in parallel to gain a better understanding of their mechanism of action."

Memorial Sloan-Kettering Cancer Center and Columbia University jointly hold the patents to SAHA and similar compounds, and license the drug to Aton Pharma Inc., which was founded by two of the study's co-authors.

Source: Proceedings of the National Academy of Sciences 2003: 10.1073/pnas.04378700100.

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