RICHMOND, Calif., Nov. 12, 2013 /PRNewswire/ -- Sangamo BioSciences, Inc. (NASDAQ: SGMO) announced today that positive preclinical data from their joint program with Shire plc to develop a novel ZFP Therapeutic® approach to Huntington's disease (HD) were presented at the 2013 Annual Meeting of the Society for Neuroscience. The meeting, which is world's largest forum for neuroscientists, is being held in San Diego from November 9-13, 2013.
The data demonstrate that Sangamo's zinc finger DNA-binding protein (ZFP) gene regulation technology can be used to selectively repress the expression of the mutant and disease-causing form of the huntingtin gene (HTT) leaving the normal gene unchanged in a mouse model (R6/2) of the disease. This selective repression has positive effects on both molecular markers and physical indications of disease in the animals. In the ZFP Therapeutic-treated regions of the animals' brains, scientists observed a reduction of mutant huntingtin protein aggregates, levels of which are associated with the severity of the disease in humans. Sangamo scientists also observed increased levels of biomarkers indicative of protection of critical nerve cells that are progressively lost in the brains of HD patients. Delivery of the ZFP Therapeutic to the brain of R6/2 mice resulted in a statistically significant reduction in "clasping behavior" compared to controls. "Clasping" is an HD-associated symptom exhibited by R6/2 animals that mimics the motor symptoms of the human disease.
"Huntington's disease is a monogenic disease with a distinct DNA signature and we believe that ZFP technology, which is highly specific and functions at the DNA level, provides the best therapeutic approach to address this intractable disease," stated Philip Gregory, D. Phil., Sangamo's vice president of research and chief scientific officer. "We are very pleased with the progress of this program and particularly these encouraging preclinical data. With Shire we are committed to developing treatment options for conditions that have significant unmet patient need, such as HD."
Sangamo's ZFP Therapeutic for Huntington's disease HD is caused by a mutation in a single gene, the huntingtin (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 well-documented that the greater the number of CAG repeats, the earlier the onset of HD symptoms.
Research in animal models of the disease has shown that lowering 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 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 TFs) targeting the expanded CAG repeat, the genetic signature of HD. 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; in turn, this achieved similar selective reduction in levels of mutant protein compared to normal HTT protein.
Delivery of these ZFP TFs to a region of the brain, the striatum, in mouse models of the disease, resulted in a statistically significant decrease (p<0.001) in production of the mutant huntingtin but not the normal form of the protein. ZFP-treatment also resulted in biomarker changes indicative of preservation of medium spiny neurons, the nerve type in the striatum that is primarily lost in HD, as well as a reduced appearance of aggregates of mutant huntingtin protein, which are thought to be a major cause of nerve dysfunction. Importantly, these molecular changes were accompanied by statistically significant improvements (p<0.05), compared to controls, in "clasping behavior" symptoms in the mouse model that mimic the motor symptoms of the human disease.
Strong support of the prospective safety of this approach was provided by a genome-wide expression analysis that confirmed that the exquisite specificity of the ZFP TFs was targeted to the HTT CAG-repeat alone.
"These data highlight the versatility and specificity of Sangamo's zinc finger technology platform," stated Edward Lanphier, Sangamo's president and CEO. "We have demonstrated that by intervening directly at the level of the mutated DNA we can achieve a selective and potent effect on the expression of the mutant gene that translates to molecular and symptomatic improvements in animal models. We are very pleased to be working with Shire to develop this ZFP Therapeutic for patients with HD."
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, develop between 35 and 44 years of age, but can start earlier. 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.
About Sangamo Sangamo BioSciences, Inc. is focused on research and development of novel DNA-binding proteins for therapeutic gene regulation and genome editing. The Company has ongoing Phase 2 and Phase1/2 clinical trials to evaluate the safety and efficacy of a novel ZFP Therapeutic® for the treatment of HIV/AIDS. As part of its acquisition of Ceregene Inc., Sangamo acquired a fully-enrolled and funded, double-blind, placebo-controlled Phase 2 trial to evaluate NGF-AAV (CERE-110) in Alzheimer's disease. Sangamo's other therapeutic programs are focused on monogenic diseases, including hemophilia, Huntington's disease and hemoglobinopathies such as beta-thalassemia and sickle cell anemia. Sangamo's core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs). Engineering of ZFPs that recognize a specific DNA sequence enables the creation of sequence-specific ZFP Nucleases (ZFNs) for gene modification and ZFP transcription factors (ZFP TFs) that can control gene expression and, consequently, cell function. Sangamo has entered into a strategic collaboration with Shire to develop therapeutics for hemophilia, Huntington's disease and other monogenic diseases and has established strategic partnerships with companies in non-therapeutic applications of its technology including Dow AgroSciences and Sigma-Aldrich Corporation. For more information about Sangamo, visit the company's website at www.sangamo.com
ZFP Therapeutic® is a registered trademark of Sangamo BioSciences, Inc.
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, the potential of Sangamo's ZFP technology to treat Huntington's disease, 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 discussion of these and other risks, please see Sangamo's public filings with the Securities and Exchange Commission, including the risk factors described in its Annual Report on Form 10-K and its most recent Quarterly Report on Form 10-Q. Sangamo assumes no obligation to update the forward-looking information contained in this press release.
SOURCE Sangamo BioSciences, Inc.