‘Zinc Fingers’ Gene Therapy Technique Succeeds in Reducing Neurotoxic Tau in Mice

Tau is a protein that misfolds in Alzheimer’s disease, causing it to accumulate and aggregate in the brain, contributing to cognitive decline. Mice engineered to lack tau are protected from neuronal damage, and when levels of tau are reduced in mouse models of Alzheimer’s, their memory improves. Therefore, reducing tau may be a good therapeutic option for AD.

What: Reducing levels of tau protein in adult mouse brains reverses neuron damage and protects against amyloid-related neurotoxicity

Where: Wegmann S et al, Persistent Repression of Tau in the Brain Using Engineered Zinc Finger Protein Transcription Factors, Science Advances, 2021.

BrightFocus Connection: Sarah L. DeVos, PhD, of Harvard-affiliated Massachusetts General Hospital, a co-first author of this paper, was partially funded with a postdoctoral fellowship grant from the BrightFocus Alzheimer’s Disease Research program. Senior author Bradley T. Hyman MD, PhD, was her fellowship mentor and also is past recipient of several BrightFocus ADR grants, including $1 million BrightFocus ADR Centennial Award in 2007, which he shared with David Holtzman, MD, of Washington University in St. Louis and Ben Barres, PhD, of Stanford University (now deceased).

Why It Is Important: Tau is a protein that misfolds in Alzheimer’s disease, causing it to accumulate and aggregate in the brain, contributing to cognitive decline. Mice engineered to lack tau are protected from neuronal damage, and when levels of tau are reduced in mouse models of Alzheimer’s, their memory improves. Therefore, reducing tau may be a good therapeutic option for AD. Now, researchers at Massachusetts General Hospital reduced tau protein in mice by 50-80 percent and the effect lasted for the entire length of the study: eleven months.

They used a genetic engineering approach to lower the expression of tau with a hybrid protein called a zinc finger protein transcription factor (ZFP-TF). It has two domains: the zinc finger and the transcription factor. The zinc finger protein can be designed to recognize any stretch of DNA that the researcher wishes; in this case, it recognizes the tau gene (MAPT), and the researchers engineered the TF to suppress the transcription of tau protein. Importantly, ZFP-TFs bind to, but do not edit, genomic sequences, making them better therapeutic candidates compared to other genetic engineering techniques.

These researchers injected a virus expressing ZFP-TFs that target the gene that makes tau protein (MAPT). The virus was injected either directly into the hippocampus, a brain region involved in learning and memory that is affected by tau pathology in neurodegenerative diseases, or more importantly for human translation, intravenously to determine whether the virus would cross the blood brain barrier and have beneficial effects in the brain. In both cases, a single injection diminished levels of tau protein by 50-80% in the brain within two weeks and the effect lasted for the duration of the study which, was almost one year.. Fewer dystrophies developed in the brains of treated mice, and their neurons were protected from toxicity.

While more research is needed to move this promising technique into the clinic, this work provides further evidence that reducing the harmful tau protein in the brain, even after neurodegeneration has begun, can be clinically beneficial and well tolerated by people suffering from Alzheimer’s. A disease modifying therapy that involves only one treatment makes the approach even more appealing