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
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
) 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
, 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
gene, which encodes a protein of the same name. Most patients inherit one normal and one defective or mutant copy of the
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
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
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
messenger RNA (mRNA) by >90% while leaving the levels of the normal
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.