The data demonstrate that a ZFP Therapeutic, based on Sangamo's zinc finger DNA-binding protein (ZFP) gene regulation technology, can selectively repress the expression of the mutant disease-causing form of the huntingtin gene (HTT) while leaving expression levels of the normal gene unchanged in cells derived from HD patients.
"This novel approach to selective and specific targeting of DNA in HD adds to the ways we can use our technology to develop innovative ZFP Therapeutics, working at the level of the genome to treat a diverse range of diseases," stated
"CHDI is always looking to ensure there is diversity in the therapeutic approaches for HD. Since expression of wild-type huntingtin appears to be essential in development, agents that selectively repress only the mutant form of the protein that cause this devastating disease should be part of the HD therapeutic pipeline," said
HD is caused by a particular type of mutation in a single gene, the HTT gene, which encodes a protein of the same name. Most patients inherit one normal and one defective or mutant copy of the HTT gene, which is enough to cause HD. The mutation is characterized by expansion of a repeated stretch of DNA sequence within the gene called a "CAG repeat." A normal copy of the HTT gene usually has 10 to 29 of these CAG repeats but a defective copy has many more — generally greater than 39 repeats. While the protein produced by the normal copy of the gene appears to be essential for development (mice lacking the gene do not survive to birth), the product of the mutated gene is damaging to nerve cells. It is known that the greater the number of CAG repeats, the earlier the onset of symptoms of Huntington's disease.
Research in animal models of the disease has shown that lowering the levels of the defective HTT protein can prevent, or even reverse, disease progression. However, to date most "HTT-lowering" methods decrease levels of both the normal and mutant forms of HTT, raising potential safety concerns given the possible importance of normal HTT protein. Sangamo's ZFP approach is unique in that it selectively shuts down the disease-causing HTT gene copy at the DNA-level while preserving activity of the normal gene copy.
Sangamo scientists designed and engineered zinc finger transcription factors (ZFP TF) targeting the genetic signature of HD, the expanded CAG repeat. In multiple independent cell lines derived from HD patients carrying different, disease-causing CAG repeat lengths, they demonstrated that these ZFP TFs decreased production of the mutant HTT messenger RNA (mRNA) by > 90% while leaving the levels of the normal HTT mRNA largely unchanged (a reduction of 10% or less); in turn, this achieved similar selective reduction in levels of mutant compared to normal HTT protein. Furthermore, in neurons derived from a HD mouse model (R6/2), ZFP TFs selectively repressed the expression of mutant HTT, which is required for disease expression in these animals. In strong support of the safety of this approach, an unbiased genome-wide expression analysis confirmed the exquisite specificity of the ZFP TFs targeted to the HTT CAG-repeat alone.
"The data presented at Neuroscience 2012 highlight our ability, using zinc finger technology, to intervene in HD specifically and directly at the level of the mutated DNA," stated
About Huntington's Disease
Huntington's disease is an inherited, progressive neurologic disease for which there is no treatment or cure. Symptoms, which include deterioration of muscle control, cognition and memory, usually develop between 35 and 44 years of age. HD is usually fatal within 10 to 20 years after the onset of symptoms. The disease has a high prevalence for an inherited disorder, affecting approximately 30,000 people (one in 10,000) in the US. An additional 150,000 people in the U.S. carry a 50% risk of developing the disease.
ZFP Therapeutic® is a registered trademark of
This press release may contain forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation, references relating to research and development of novel ZFP TFs and ZFNs and therapeutic applications of Sangamo's ZFP technology platform and Sangamo's collaboration with Shire for the treatment of Huntington's disease and other inherited genetic diseases. Actual results may differ materially from these forward-looking statements due to a number of factors, including uncertainties relating to the initiation and completion of stages of our clinical trials, whether the clinical trials will validate and support the tolerability and efficacy of ZFNs and ZFP TFs, technological challenges, Sangamo's ability to develop commercially viable products and technological developments by our competitors. For a more detailed
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