Researchers at the DZNE (Germany), at Massachusetts General Hospital (USA) and at the genomic medicine company Sangamo Therapeutics, Inc. tested a novel gene regulation approach to treat brain diseases such as Alzheimer's in laboratory studies. It leverages zinc finger proteins, which specifically bind to the DNA that codes for the protein Tau without altering it, thereby reducing Tau production in the brain and preventing nerve damage. The preclinical results, published in the journal Science Advances, could lay the foundation for new therapies.

The Tau protein plays a key role in the development of certain degenerative brain diseases called tauopathies. Tau accumulates and aggregates within nerve cells, causing destruction of synapses and cell death. The consequence is a progressive dysfunction of cognitive, motor and psychological abilities.

Results of new research published in the journal Science Advances demonstrate that a gene regulation therapy using zinc finger protein transcription factors (ZFP-TFs) provides sustained Tau protein reduction in the brain when administered to a preclinical mouse model of Alzheimer's disease, one of the most studied tauopathies. A one-time intravenous or intracranial administration of tau-targeted ZFP-TFs decreased tau levels by 50 to 80% out to 11 months, the longest time point studied. The zinc finger technology was developed by Sangamo Therapeutics and has now been applied by the researchers to reduce Tau protein in the adult brain.It could be the starting point for a new generation of treatments for tauopathies such as Alzheimer's disease and frontotemporal dementia.

Preclinical studies show high efficacy with no obvious side effects

According to Susanne Wegmann, head of a research group at the DZNE in Berlin, the results of the study, performed in adult mice, indicate that nerve cells appear to be protected against early toxic effects of amyloid-beta if Tau has been reduced by the Tau-targeted zinc finger proteins: "Under certain conditions, such as Alzheimer's disease, Tau proteins can have the effect of a cell toxin. Thus, there is an ongoing effort to reduce their amount in the brain," Wegmann explains. Nerve cell damage occurs first in the vicinity of amyloid plaques, which are, next to Tau, the other kind of protein accumulation found in Alzheimer's disease brains.

Wegmann and colleagues were now able to prevent this by reducing Tau with this approach. "Nerve cells normally produce Tau proteins. With the help of zinc finger protein technology, we have now been able to achieve a long-lasting reduction of Tau production, and thereby significantly reduce the toxic effects of the plaques," Wegmann explains. Of additional importance is that the long-lasting Tau reduction did not cause obvious side effects or changes in tissue structure in the brains of treated mice.

In this publication, we demonstrate that ZFP-TFs can reduce Tau mRNA and proteins in neurons both acutely and long-term in the adult brain. With this, we can achieve a long-lasting effect upon a single injection of therapeutic adeno-associated viruses, with no obvious neurotoxic side effects."

Susanne Wegmann, DZNE Researcher

Zinc finger technology as a starting point for future therapies in humans

Zinc finger proteins can be engineered to bind very specifically to unique gene sequences within the cell and reduce or silence their expression. In this work, they were programmed to precisely bind to sequences in the genetic code for the Tau protein. Thus, the transcription of these sequences, and consequently the production of the Tau protein, is blocked; as a result, the total amount of Tau decreased by 50 to 80% throughout the brain. Unlike gene-editing approaches, which cut or change the DNA itself, ZFP-TFs induce long-term changes in Tau expression without altering the genetic material of the cells in the process.

The nerve cells do not produce the zinc finger protein naturally, but are made to do so with a biotechnological technique – by introducing the blueprint for this substance into the cells via an engineered virus. These AAVs cannot multiply or spread, and instead serve as a useful delivery mechanism for the ZFP-TF to reach its destination within the brain. The cell's natural machinery then continuously produces the ZFP-TF proteins – over a long period of time – to block the Tau gene. In this way, a single treatment is likely to be sufficient to reduce the Tau protein for the long term.

"These compelling results published in Science Advances demonstrate the potential of our highly specific and efficient zinc finger protein transcription factor technology for treating neurologic disease," said Bryan Zeitler, Director of Gene Regulation at Sangamo. "There are currently no disease-modifying thereapies approved for patients with Alzheimer's disease or other tauophathies. This publication represents the promise of Sangamo's zinc finger protein transcription factor approach to potentially provide a one-time treatment to slow or stop disease progression."

The results serve as basis for further development of the technology and for clinical research in humans. The pharmaceutical company Biogen has a global collaboration agreement with Sangamo to develop gene regulation therapies based on this approach and the Companies are progressing toward the clinic.