Sangamo is developing a ZFP TF-mediated gene repression therapeutic approach for Huntington's disease as part of our collaboration with Shire. Preclinical studies in animal models of the disease are ongoing.
Huntington’s disease (HD) is an inherited, progressive neurologic disease for which there is no treatment or cure. The disease is caused by a particular type of mutation in a single gene, the HTT gene. Most patients inherit one normal and one defective or mutant copy of the HTT gene, which causes 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.
Symptoms, which include deterioration of muscle control, cognition and memory, develop between 35 and 44 years of age. It is known that the greater the number of CAG repeats, the earlier the onset. HD is usually fatal within 10 to 20 years after the onset of symptoms. The disease has a high prevalence for an inherited disorder. According to the Huntington's Disease Society of America (HDSA) one in 10,000 people in the U.S. has HD (approximately 30,000 people). In addition, it is estimated that approximately 200,000 people in the U.S. are at risk of developing the disease.
Sangamo's Therapeutic Approach
Research in animal models of the disease has shown that lowering the levels of the mutant 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. In collaboration with Shire, we are developing ZFP TFs that can selectively repress the expression of the mutant disease-causing form of HTT while leaving expression levels of the normal gene unchanged.