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Vol 8. Issue 27 / September 22, 2008
By Renee Twombly
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.
"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 Assistant Professor Elizabeth A. Thomas, who led the new research.
Photo by Dana Neibert.
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."
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.
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. Adleson Medical Research Foundation, and funding from Repligen Corporation.For more information on Thomas's work, see the Thomas faculty page, and the article, "Genes of the Mind," in the Fall 2008 (Volume 11, Number 2) issue of Endeavor.
If you feel like reading an unputdownable novel while collaborating with a just and solidary cause, "The Legacy of Marie Schlau" is your book! 100% of all funds raised will be dedicated to medical research to find a cure for Friedreich's Ataxia, a neurodegenerative disease that affects mostly young people, shortening their life expectancy and confining them to a wheelchair.
The life of Marie Schlau, a German Jewish girl born in 1833 hides great unsolved mysteries: accidents, disappearances, enigmas, unknown diagnoses, disturbing murders, love, tenderness, greed, lies, death ... alternatively a different story unfolds every time and takes us closer to the present. Thus, there are two parallel stories unravelling, each in a different age and place, which surprisingly converge in a revelatory chapter.
Paperback and Kindle versions for "The legacy of Marie Schlau" available for sale at Amazon now!
Currently, BabelFAmily is financing two promising research projects aimed at finding a cure for Friedreich's Ataxia. Whenever you make a donation to us or purchase a copy of "The legacy of Marie Schlau", this is where all funds raised will be devoted to:
1) Gene Therapy for Friedreich's Ataxia research project:
The project is the result of an initiative of Spanish people affected by this rare disease who are grouped in GENEFA in collaboration with the Spanish Federation of Ataxias and the BabelFAmily. The Friedreich’s Ataxia Research Alliance (FARA), one of the main patients’ associations in the United States now joins the endeavour.
2) Frataxin delivery research project:
The associations of patients and families Babel Family and the Asociación Granadina de la Ataxia de Friedreich (ASOGAF) channel 80,000 euros of their donations (50% from each organisation) into a new 18-month project at the Institute for Research in Biomedicine (IRB Barcelona). The project specifically aims to complete a step necessary in order to move towards a future frataxin replacement therapy for the brain, where the reduction of this protein causes the most damage in patients with Friedreich’s Ataxia.
The study is headed by Ernest Giralt, head of the Peptides and Proteins Lab, who has many years of experience and is a recognised expert in peptide chemistry and new systems of through which to delivery drugs to the brain, such as peptide shuttles—molecules that have the capacity to carry the drug across the barrier that surrounds and protects the brain. Since the lab started its relation with these patients’ associations in 2013*, it has been developing another two projects into Friedrich’s Ataxia.