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Sangamo Presents Dramatic Data Indicating Their ZFP Enzymatic Approach Can Prevent and Reverse Pathogenic Accumulation of Mutant Protein in Huntington’s Disease in Animal Models; Wexler Terms Results a “Significant Step Forward”

On November 19, 2014, Sangamo BioSciences, Inc., announced its presentation of positive preclinical data from its joint program with Shire plc, to develop a novel ZFP (zinc-finger protein) Therapeutic® approach to Huntington's disease (HD), at the 2014 Annual Meeting of the Society for Neuroscience. Note that zinc fingers are proteins that normally bind at different bases in DNA in order to regulate gene activity. The dramatically exciting data were generated by Sangamo scientists and the CHDI Foundation, which is dedicated to accelerating therapeutic developments for HD. "These data are very exciting and represent a significant step forward in the quest for a therapeutic for Huntington's disease," said Nancy Wexler, Ph.D., Higgins Professor of Neuropsychology in the Departments of Neurology and Psychiatry of the College of Physicians and Surgeons at Columbia University, and the President of the Hereditary Disease Foundation. "They provide the first demonstration of a therapeutic approach that can not only prevent, but reverse the accumulation of mutant Huntingtin protein aggregates in the brains of animal models of the disease. Furthermore, the treatment does not affect the expression of the normal form of the protein, which is believed to be essential." The mutant form of the Huntingtin protein (Htt) accumulates in cells and forms protein aggregates which are associated with disease symptoms. Pioneering basic research in transgenic animal models has shown that the levels of the defective Htt protein correlate with disease progression, stimulating the search for strategies to reduce mutant Htt levels as a therapeutic intervention. However, most "Htt-lowering" methods decrease the levels of both disease-causing and normal forms of Htt. Decreasing the levels of normal Htt raises concerns as the protein appears to be essential and mice lacking Htt die before birth. "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. This translates to molecular and symptomatic improvements in several animal models and patient-derived cells that span the full range of mutations relevant to human disease," stated Philip Gregory, D. Phil., Sangamo's Senior Vice President of Research and Chief Scientific Officer.

"Huntington's disease is a monogenic disease with a distinct DNA signature and we believe the application of our ZFP technology, which functions at the DNA level, provides the best therapeutic approach to address this intractable disease."

Data presented at Neuroscience 2014 demonstrated that Sangamo's zinc finger DNA-binding protein (ZFP) gene regulation technology can selectively repress expression of the mutant form of the huntingtin gene (HTT) which causes the disease, while leaving the normal gene largely unchanged in both patient-derived cells and in several mouse models. Importantly, the data also demonstrated the selective effects over the full range of HTT mutations relevant to human disease.

When delivered to the brain in an animal model of the disease, the ZFP Therapeutic not only prevented formation of aggregates if administered at early time points in disease progression, but reversed aggregate formation when administered at later time points. The effects observed in both cases were statistically significant (p < 0.001).

ZFP treatment of the animals also maintained expression of markers of medium spiny neurons, a particular class of nerve cell in the striatum of the brain primarily lost in patients with HD. In addition, ZFP treatment reversed physical indications of disease as manifest in a statistically significant reduction in "clasping behavior" compared to controls (p=0.015). "Clasping" is an HD-associated symptom exhibited by a mouse model of HD (R6/2) that mimics the motor symptoms of the human disease.

ZFP-mediated selective repression of mutant HTT had statistically significant positive effects on the health of HD-patient-derived nerve cells as measured by several molecular markers. These effects included an increase in indicators of cellular metabolism and protection of the cells from programmed cell death when growth factors were withdrawn from the culture medium (p < 0.01). Strong support for the prospective safety of this approach was provided by a genome-wide expression analysis that confirmed that the exquisite specificity of the mutant HTT-targeted ZFP transcription factor (TF).

"These data highlight the exquisite specificity that can be achieved with Sangamo's zinc finger technology platform," stated Edward Lanphier, Sangamo's President and CEO. "We are very pleased with the progress of this program and to be working with Shire to develop this ZFP Therapeutic for patients with HD."

HD is caused by a mutation in a single gene, the huntingtin (HTT) gene, which encodes a protein of the same name, huntingtin. 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 more 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.

Sangamo scientists designed and engineered zinc finger protein 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, the Sangamo scientists 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.

HD is an inherited, progressive neurologic disease for which there is presently no treatment or cure. Symptoms, which include deterioration of muscle control, cognition, and memory, typically 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 higher-than-usual prevalence for an inherited disorder, affecting approximately 30,000 people (one in 10,000) in the United States. An additional 150,000 people in the U.S. carry a 50% risk of developing the disease.

[Press release] [Sangamo BioSciences]