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Innovative screening method identifies possible new treatment for fatal childhood disease
Date:4/18/2011

esterification is the formation of esters, fatty compounds derived from acids). The discovery of a new use for a drug already on the market is always good news, as the drug has already been tested for safety.

Sturley and his team took advantage of the fact that the gene responsible for 95% of NP-C cases has been present throughout evolution, including in the evolutionarily distant yeast. They used what is called a "synthetic lethality screen" on a yeast model of NC-P. Synthetic lethality occurs when the combination of otherwise insignificant mutations in two or more genes leads to cell death. In other words, they determined which combination of mutations was lethal to the yeast.

The cell nucleus contains proteins called histones. During histone acetylation, a group of atoms called an acetyl group is substituted for a hydrogen atom, and during histone deacetylation, it is removed. When deletion of genes responsible for histone acetylation in the yeast model led to an accumulation of lipids, the researchers hypothesized that an imbalance in histone acetylation caused NP-C disease.

They found that the majority of the 11 histone deacetylase (HDAC) genes were impaired. They then discovered that the cancer drug, an HDAC inhibitor, repaired the genes. Sturley and his team concluded that the genetic pathways that exacerbate lethality in the yeast model could be reversed in human cells, providing a novel treatment for NP-C. In short, using their "exacerbate-reverse" approach, they identified the pathways that exacerbate lethality in their yeast model and then used drugs to manipulate those pathways in the opposite direction.

The next step is to test this new use of the cancer drug on mice and, eventually, hopes Sturley, in clinical trials. Although scientific curiosity originally led Sturley to study NP-C, he is now motivated by the search for a cure. "Once you get to know some of these kids and their families," he says, "it can't be othe
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Contact: Ann Rae Jonas
arj2116@columbia.edu
212-305-3900
Columbia University Medical Center
Source:Eurekalert

Page: 1 2 3

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