Approach Selectively Represses Only the Disease-Causing Gene Resulting in Statistically Significant
Effects on Symptoms and Other Biomarkers of Disease in Animal Models
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
Source: Sangamo BioSciences