Gene Therapy Using ‘Zinc Fingers’ May Help Treat Alzheimer’s Disease

Summary: A new genetic engineering strategy significantly reduces levels of tau in animal models of Alzheimer’s disease. The treatment, which involves a single injection, appears to have long-last effects.

Source: Mass General

Researchers have used a genetic engineering strategy to dramatically reduce levels of tau–a key protein that accumulates and becomes tangled in the brain during the development of Alzheimer’s disease–in an animal model of the condition.

The results, which come from investigators at Massachusetts General Hospital (MGH) and Sangamo Therapeutics Inc., could lead to a potentially promising treatment for patients with this devastating illness.

As described in Science Advances, the strategy involves a gene regulation technology called zinc finger protein transcription factors (ZFP-TFs), which are DNA-binding proteins that can be harnessed to target and affect the expression of specified genes. In this case, the therapy was designed to target and silence the expression of the gene that codes for tau.

Mice with Alzheimer’s disease received a single injection of the treatment–which employed a harmless virus to deliver the ZFP-TFs to cells–directly into the hippocampus region of the brain or intravenously into a blood vessel.

Treatment with ZFP-TFs reduced tau protein levels in the brain by 50% to 80% out to 11 months, the longest time point studied. Importantly, the therapy reversed some of the Alzheimer’s-related damage that was present in the animals’ brain cells.

This shows a brain
The simplicity of the therapy makes it an especially attractive approach. Image is in the public domain

“The technology worked just the way we had hoped–reducing tau substantially for as long as we looked, causing no side effects that we could see even over many, many months, and improving the pathological changes in the brains of the animals,” says senior author Bradley Hyman, MD, PhD, who directs the Alzheimer’s disease research unit at the MassGeneral Institute for Neurodegenerative Disease. “This suggests a plan forward to try to help patients.”

The simplicity of the therapy makes it an especially attractive approach. “This was the result of a single treatment of gene regulation therapy, which could be given by an injection into the bloodstream,” says Hyman. “While this therapy is far from patients–as much more development and safety testing would need to be done–it is a promising and exciting first step.”

Funding: The study was primarily supported by Sangamo, pursuant to a sponsored research agreement with MGH. Funding was also provided by MGH and the German Center for Neurodegenerative Diseases (DZNE) of the Helmholtz Foundation, the JPB Foundation, the National Institute on Aging, and the BrightFocus Foundation.

About this genetics and Alzheimer’s disease research news

Source: Mass General
Contact: Michael Morrison – Mass General
Image: The image is in the public domain

Original Research: Open access.
Persistent repression of tau in the brain using engineered zinc finger protein transcription factors” by Bradley Hyman et al. Science Advances


Persistent repression of tau in the brain using engineered zinc finger protein transcription factors

Neuronal tau reduction confers resilience against β-amyloid and tau-related neurotoxicity in vitro and in vivo.

Here, we introduce a novel translational approach to lower expression of the tau gene MAPT at the transcriptional level using gene-silencing zinc finger protein transcription factors (ZFP-TFs).

Following a single administration of adeno-associated virus (AAV), either locally into the hippocampus or intravenously to enable whole-brain transduction, we selectively reduced tau messenger RNA and protein by 50 to 80% out to 11 months, the longest time point studied.

Sustained tau lowering was achieved without detectable off-target effects, overt histopathological changes, or molecular alterations. Tau reduction with AAV ZFP-TFs was able to rescue neuronal damage around amyloid plaques in a mouse model of Alzheimer’s disease (APP/PS1 line).

The highly specific, durable, and controlled knockdown of endogenous tau makes AAV-delivered ZFP-TFs a promising approach for the treatment of tau-related human brain diseases.

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