Sangamo Therapeutics‘ gene regulation technology significantly reduced levels of tau – a protein crucial to Alzheimer’s disease (AD) – in laboratory tissue experiments and a mouse model, the company announced.
Sangamo’s collaborators from the Massachusetts General Hospital Alzheimer’s Disease Research Center and Harvard Medical School presented the results at the 13th International Conference on Alzheimer’s & Parkinson’s Diseases in Vienna.
In addition to extracellular amyloid plaque, accumulation of tau protein and neurofibrillary tangles in the brain are hallmarks of Alzheimer’s. The tangles ultimately lead to neuronal dysfunction and loss. Reducing tau levels protects neurons and may reverse the disease, research has shown.
“Tau protein plays a critical role in certain devastating neurodegenerative diseases, including dementias such as AD, and studies point to the potential for tau reduction to prevent neuronal loss and possibly even reverse Alzheimer’s disease pathology,” Bradley Hyman, MD, PhD, said in a press release. Hyman is the director of the Massachusetts Alzheimer’s Disease Research Center and of the Alzheimer’s Unit at the MassGeneral Institute for Neurodegenerative Disease. He is also a neurology professor at Harvard Medical School.
The study involved Sangamo’s zinc finger protein transcription factor (ZFP-TF)-mediated gene regulation technology. ZFP-TF selectively represses or activates the expression of a specific gene or gene sequence. That makes it different from approaches such as genome editing or gene therapy, which aim to correct or replace a missing or mutated gene.
Importantly, ZPF-TF can be applied to a broad range of diseases.
“Of the many approaches to reduce tau expression that we’ve studied, zinc finger protein gene regulation technology is especially promising for its exquisite specificity, its potent reduction of tau protein expression, and its potential to provide a durable, long-lasting effect with only a single administration,” Hyman said.
Laboratory-tissue, or in vitro, experiments demonstrated that a single administration of ZFP-TFs resulted in a greater than 90% reduction in tau messenger RNA (mRNA) and protein in neurons derived from either wild mice or stem cells. Further analysis showed this effect was specific because tau was the only gene suppressed out of a more than 26,000-gene sample.
Additionally, in vivo studies in normal mice demonstrated a greater than 80% reduction of tau mRNA and protein in the hippocampus. That part of the brain, which is vital to regulating learning and memory, is severely affected in Alzheimer’s.
Researchers also found ZFP-TF expression to be sustained and well-tolerated, with minimal impact on inflammatory markers. In addition, a single administration of ZFP-TFs significantly reduced the presence of key neuropathological markers of dementia in an amyloid mouse model of Alzheimer’s.
ZPF-TF’s precision and potency in lowering tau indicates that it is a promising therapeutic approach for neurodegenerative diseases, researchers said.
“Our zinc finger protein transcription factor technology continues to demonstrate great potential as a highly differentiated, best-in-class genomic therapy platform for neurodegenerative diseases,” said Michael Holmes, PhD, Sangamo’s vice president and head of research. “ZFP-TFs allow us to selectively repress the tau gene, which results in significant reduction of all forms of the tau protein, in contrast to other monoclonal antibody-based approaches to AD and tauopathies that bind only to specific forms of tau.”
Sangamo intends to partner with a disease expert to develop ZPF-TF technology for Alzheimer’s and other neurodegenerative diseases associated with tau aggregation. Sangamo is developing ZFP-TF for Huntington’s disease in partnership with Shire.