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Scripps Research Team Reverses Huntington's Disease Symptoms in Mice

Experimental Treatment is Being Readied for Further Testing

LA JOLLA , CA, September 15, 2008—There is no cure for Huntington's disease, or even treatments that can reverse or slow progression of the devastating movement deficits and cognitive dysfunction that occur with the condition. But, now, an agent developed by scientists at The Scripps Research Institute has shown dramatic therapeutic efficacy in experimental mice, and did so with minimal toxicity.

In the Early Edition of the Proceedings of the National Academy of Sciences (PNAS) during the week of September 15, 2008, the team describes how the inhibitor, HDACi 4b, dramatically improved the physical appearance and motor functioning of Huntington's disease transgenic mice, and retarded their loss of body weight and reduction of brain size.

"The benefit seen was surprising, and immensely exciting, because it suggests this compound could form the basis of a truly relevant therapeutic treatment for Huntington's disease," says the study's lead author, Elizabeth A. Thomas, Ph.D., Assistant Professor in the Scripps Research Department of Molecular Biology. "The mice that were destined to develop Huntington's disease receiving the treatment did significantly better than the mice who didn't receive the drug."

Hundreds of Genes
The source of Huntington's disease is a mutated gene caused by a trinucleotide repeat expansion—a sequence of three DNA bases (CAG) repeated multiple times. The protein this gene produces is misfolded and cannot function correctly. For reasons not well understood, this series of events causes widespread changes in the transcription of hundreds of genes throughout the brain, leading to issues ranging from jerky and random movements to impaired thinking and perception.

In mice whose genome has been modified to contain a mutant human Huntington's disease gene, such symptoms develop when the mice are about three months old. In the new study, the researchers administered HDACi 4b to such mice after symptoms first appeared, adding the agent to the drinking water when the mice were four months of age. This is reminiscent of the human condition where patients are often diagnosed after symptom presentation.

HDACi 4b is among a class of agents called histone deacetylase (HDAC) inhibitors, which are known to help control gene transcription. While other agents in this class have been tested on models of Huntington's disease with some beneficial results, previous compounds were ultimately too toxic for use as a treatment.

In the new study, the Scripps Research scientists modified an HDAC inhibitor that was already commercially available. HDACi 4b's development was spearheaded by senior author Scripps Research Professor Joel Gottesfeld, Ph.D., who in 2006 created and published a small library of HDAC compounds he believed would be specific for brain disorders caused by triple repeats. Several patent applications related to these compounds have been exclusively licensed to Repligen Corporation in Waltham, Massachusetts, which is conducting further testing and development.

HDAC inhibitors work by removing the barrier that a mutant protein can place on gene transcription. If a gene can't be "read," it can't be transcribed in order to produce its protein. This process occurs in the chromatin, which is the complex of genes and proteins that make up the chromosomes. The main proteins in chromatin are the histones, which act like spools around which DNA can wind itself into the chromosomes in order to fit within the cell's nucleus.

In order for transcription to occur, the chromatin needs to "relax" and open up so that the gene can be available. This relaxation occurs when chemicals known as acetyl groups attach to the histones —a reaction called acetylation. When chromatin is condensed, unavailable for transcription, the histones are said to be "de-acetylated" by enzymes called de-acetylases. HDAC inhibitors stop the acetyl groups from being removed from histones, causing the chromatin to open up for transcription.

More Effective, Less Toxic

In the new study, HDACi 4b was tested on Huntington's disease mice for its ability to ward off motor deficits and neurodegeneration in treated mice, as well as for its toxicity. "The agent proved to be therapeutically superior, as well as less toxic than other HDAC inhibitors that had been tested for Huntington's disease," Thomas says.

The researchers also found, using gene microarrays, that their agent substantially altered gene expression in the brain. The scientists looked at the top genes that were altered in the brain's striatum, which is where many of the Huntington's disease deficits show up, and found that 77 of the top 142 down-regulated genes and 39 of the top 80 up-regulated genes in the mice also showed expression changes in the caudate of human patients with Huntington's disease. When expression of 600-plus genes from three brain areas were examined, 85 to 94 percent of the genes, depending on the region, were partially normalized with HDACi 4b treatment, with one-third being completely restored to a normal status.

"We found that one drug can target expression of a several hundred genes in the brain and reverse the abnormalities caused by a single mutant protein," Thomas says. "This suggests that a treatment for Huntington's disease that targets a core pathogenic mechanism might be close at hand – closer than previously imagined."

In addition to Thomas and Gottesfeld, authors of the study, "The HDAC Inhibitor 4b Ameliorates the Disease Phenotype and Transcriptional Abnormalities in Huntington's Disease Transgenic Mice," were Giovanni Coppola, Fuying Gao, and Daniel H. Geschwind of the University of California, Los Angeles, and Paula A. Desplats, Bin Tang, Elisabetta Soragni, Ryan Burnett, Kelsey M. Fitzgerald, Jenna F. Borok, and David Herman of Scripps Research.

The study was funded by grants from the National Institutes of Health and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and funding from Repligen Corporation.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus by 2009.


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