Submitted by Marsha Miller Ph.D. on Fri, 10/10/2008
A new HDAC inhibitor developed by Scripps Research Institute and licensed by Repligen Corporation has been found to ameliorate HD pathology in a mouse model of Huntington's Disease. Normal gene transcription was partially restored and the animals improved in movement and brain volume as compared to untreated HD mice.
Transcriptional dysregulation has been shown to be a major pathology in Huntington's Disease. The huntingtin's protein is usually found in the cytoplasm, making only brief visits to the nucleus of the cell in response to stress. The HD version of the protein with its expanded polyglutamine region begins to pile up in the nucleus of the cell where it interferes with the transcription of other genes. A large number of genes whose proteins are needed for the cell to do its work are down-regulated and a smaller number of genes that are not needed are up-regulated.
One approach to address this problem has been to look for histone deacetylase (HDAC) inhibitors that might partially correct the problem. During the process of gene expression, DNA winds around proteins called histones. Enzymes called histone acetylases facilitate transcription by making histones less compact while histone deacetylases inhibit transcription by making histones more compact.
Existing HDAC inhibitors have been tested in the mice. The results suggested that HDAC inhibition might be an effective therapeutic approach, but none of the drugs were as promising for the research pipeline as researchers would like given concerns about side effects and level of effectiveness.
The HDAC inhibitor developed at Scripps (HDACi 4b) has very positive results in the R6/2 mice. Body weight and movement was improved compared to untreated mice, brain atrophy was reduced, and gene expression was at least partially restored in 90 percent of the genes affected by transcription dysregulation. Interestingly, some genes were up-regulated but others were down-regulated, notably genes associated with cell death and the immune response.
These results are very encouraging for the HD community. They represent an improvement over previous studies with other HDAC inhibitors and they were obtained even though HDACi 4b was administered after the animals were already symptomatic. In addition, the drug is one that has already been approved for other purposes and it has minimal toxicity.
We are seeing more and more drugs being added to the HD pipeline, thanks to high throughput assays, drug development expertise, and good mouse models of the disease. It is important to remember that people are not mice and we can expect some of the these drugs and supplements to drop out of the pipeline. However, it seems equally likely that some will prove to be effective.
More than ever, we need people to volunteer for observational studies like COHORT so that biomarkers can be developed to help prioritize compounds for trials and to shorten those clinical trials. We also need people with the HD gene who are willing to volunteer for upcoming clinical trials
Transcriptional dysregulation has emerged as a core pathologic feature of Huntington's disease (HD), one of several triplet-repeat disorders characterized by movement deficits and cognitive dysfunction. Although the mechanisms contributing to the gene expression deficits remain unknown, therapeutic strategies have aimed to improve transcriptional output via modulation of chromatin structure. Recent studies have demonstrated therapeutic effects of commercially available histone deacetylase (HDAC) inhibitors in several HD models; however, the therapeutic value of these compounds is limited by their toxic effects. Here, beneficial effects of a novel pimelic diphenylamide HDAC inhibitor, HDACi 4b, in an HD mouse model are reported. Chronic oral administration of HDACi 4b, beginning after the onset of motor deficits, significantly improved motor performance, overall appearance, and body weight of symptomatic R6/2300Q transgenic mice. These effects were associated with significant attenuation of gross brain-size decline and striatal atrophy. Microarray studies revealed that HDACi 4b treatment ameliorated, in part, alterations in gene expression caused by the presence of mutant huntingtin protein in the striatum, cortex, and cerebellum of R6/2300Q transgenic mice. For selected genes, HDACi 4b treatment reversed histone H3 hypoacetylation observed in the presence of mutant huntingtin, in association with correction of mRNA expression levels. These findings suggest that HDACi 4b, and possibly related HDAC inhibitors, may offer clinical benefit for HD patients and provide a novel set of potential biomarkers for clinical assessment.
press release: Repligen Announces Publication of Positive Results with Proprietary HDAC Inhibitor in Huntington's Disease Model Study Published in the Proceedings of the National Academy of Sciences
Repligen Corporation (NASDAQ: RGEN) today reported publication of a preclinical study demonstrating that a novel histone deacetylase (HDAC) inhibitor improved disease symptoms in a transgenic animal model of Huntington's disease. The study, led by scientists at The Scripps Research Institute, demonstrated that oral administration of the drug candidate to the mice after the onset of symptoms slowed the progression of disease. Treated animals showed superior motor performance by multiple measures, reduced loss of body weight, reduced brain atrophy and improved overall appearance compared to untreated animals. Huntington's mice were also analyzed for changes in the hundreds of genes whose expression in the brain is altered in the mouse model of Huntington's, as well as in humans with Huntington's disease. Using gene microarrays, the researchers identified genes in three brain regions whose expression was altered in the Huntington's mice and whose expression was altered by treatment with the HDAC inhibitor. Treatment partially normalized the expression level of approximately 90% of these genes with 32% being restored to normal levels. These results suggest that an HDAC inhibitor may be useful in treating Huntington's disease and that specific genes may be useful as biomarkers in clinical trials. The research was conducted using a compound that is covered by Repligen's exclusive license from The Scripps Research Institute. The study entitled "The HDAC Inhibitor 4b Ameliorates the Disease Phenotype and Transcriptional Abnormalities in Huntington's Disease Transgenic Mice" will be published the week of September 15, 2008 in the online version of the Proceedings of the National Academy of Sciences.
"The marked reduction in symptoms achieved in the Huntington's disease model without overt toxicity defines a second disease target for our HDAC inhibitor program," stated Walter C. Herlihy, President and Chief Executive Officer of Repligen Corporation. "We plan to continue to evaluate the utility of our novel HDAC inhibitors as a potential treatment for both Friedreich's ataxia and Huntington's disease."
Repligen licensed the exclusive rights to intellectual property covering HDAC inhibitors from The Scripps Research Institute in April 2007 following which Repligen established a HDAC development program for Friedreich's ataxia. Over the past year, the Company has made significant progress in advancing this program, resulting in the identification of advanced lead compounds with improved potency and specificity. These lead compounds are currently being assessed in pharmacology and toxicology models in order to determine if one is suitable for clinical development. In addition to Huntington's disease, Repligen is evaluating this family of compounds for activity in preclinical models of other neurodegenerative diseases including spinal muscular atrophy.