Histone deacetylase (HDAC) inhibitors are a potential treatment for Huntington's Disease. Interest was first generated when Dr. Leslie Thompson and colleagues reported in 2001 that HDAC inhibitors arrested neurodegeneration in a fruitfly model of polyglutamine disease.
More excitement was inspired by a 2003 study carried out in the Bates lab with R6/2 HD mice which showed that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, ameliorated their motor deficits. Another study was conducted in 2003 by Dr. Robert Ferrante and colleagues with the same mouse strain but using sodium butyrate, a different HDAC inhibitor, which resulted in delayed onset, lengthened survival times, reduced oxidative stress in the neurons, and improved both body weight and motor performance.
The idea behind this potential treatment is that the HD protein is known to interfere with gene transcription. That means that the instructions don't go out to make other proteins and the cell can't do its work; it gets sick and eventually it dies. The mutant huntingtin's protein binds to the acetyltransferase domains of proteins such as CBP, thereby inhibiting the process of histone acetylation which is necessary for gene transcription to take place. The researchers reasoned that HDAC inhibitors should counteract that problem and make it possible for gene transcription to continue.
Transcription problems are an early event in the Huntington's Disease process so if further research eventually proves HDAC inhibitors to be effective with people, it would be a major treatment.
Penny Hogarth, M.D. of Oregon State Health University began recruiting last summer for a study of safe phenylbutyrate doses for HD patients. The HDSA's Spring 2003 newsletter Toward a Cure reported that Stephen Hersch, M.D, Ph.D., of Massachusetts General Hospital would conduct a larger safety and tolerability study following Dr. Hogarth's results.
It is a good sign that pharmaceutical companies want to invest in HDAC inhibitor research.
MONTREAL--(BUSINESS WIRE)--July 13, 2004--MethylGene Inc. (TSX:MYG), a biopharmaceutical company, and EnVivo Pharmaceuticals, Inc., a private U.S. biopharmaceutical company focusing on the treatment and prevention of neurodegenerative diseases, today announced that EnVivo has exercised its option to enter into an exclusive research, collaboration and license agreement to exploit MethylGene's isotypic selective small molecule histone deacetylases (HDAC) inhibitors for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease.
In March 2004, MethylGene and EnVivo entered into a proof of concept and option agreement to discover HDAC inhibitors in neurodegenerative diseases. MethylGene received a contract research payment and an upfront option fee. Upon execution of the collaboration agreement, MethylGene will receive an upfront license payment and contract research payments totaling U.S.$1.1 million. MethylGene will also receive a milestone payment based on an early stage clinical development milestone. The parties intend to jointly fund research and development and commercialization as well as equally share resulting profits, subject to opt-out provisions.
"This collaboration is consistent with our strategy to build value around our isotypic selective HDAC expertise beyond our current oncology focus. This strategy entails identifying collaborators, such as EnVivo, with excellent biology and in vivo expertise in non-oncology indications to share research, development and commercialization," said Donald F. Corcoran, President and CEO of MethylGene. "Our goal is to leverage our isotypic selective HDAC inhibitor technology in non-oncology indications by establishing proof of concept and intellectual property with partners and moving quickly toward clinical development." "Using EnVivo's proprietary humanized Drosophila discovery platform and vertebrate assays, we rapidly characterize novel compounds that may be effective as new treatments for neurodegenerative diseases. HDACs are attractive pharmaceutical targets of potential high relevance to these diseases, and we are looking forward to working with MethylGene as we move ahead with this exciting new approach," said Dr. David A. Lowe, President and CEO of EnVivo. Upon execution of the agreement, MethylGene will contribute its proprietary chemistry and functional genomics expertise for HDAC inhibitors to be further researched in collaboration with EnVivo's proprietary in vivo models and discovery platforms for neurodegenerative diseases.
About 4.5 million patients in the United States suffer from Alzheimer's disease, 1.5 million from Parkinson's disease and 30,000 from Huntington's disease. The worldwide market for drugs to treat these diseases is currently estimated at more than U.S. $3.5 billion. About HDAC
Histone deacetylases (HDAC) are a family of 11 enzymes that are involved in the regulation of gene expression and may as such be a master regulator for disease. It has been established in the scientific literature and observed by our scientists and potential collaborators that isotypic selective inhibition of HDAC enzymes may have the potential to impact diseases including cancer, diabetes, inflammation, cardiovascular and neurodegenerative diseases. It has been demonstrated that transcriptional dysregulation by HDAC may play a role in neurodegenerative disease and that HDAC therapy may prevent or slow down the neurodegenerative disease process. MethylGene is currently developing MGCD0103, an isotype selective inhibitor targeting specific HDAC enzymes involved in the regulation of tumour suppressor genes in cancer. MGCD0103 is currently in two Phase I monotherapy trials against solid tumors.
For a good scientific explanation of HDAC inhibitors visit HOPES
The original fruitfly research