Researchers are testing new gene regulation approach to treat brain disease

Researchers from DZNE (Germany), Massachusetts General Hospital (US), and genomic medicine company Sangamo Therapeutics, Inc. tested a new gene regulation approach to treat brain diseases such as Alzheimer’s disease in laboratory studies. It harnesses zinc finger proteins, which specifically bind to DNA that encodes the Tau protein without modifying it, thereby reducing Tau production in the brain and preventing nerve damage. The preclinical results, published in the journal Scientific progress, could lay the foundations for new therapies.

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

Results of new research published in the journal Scientific progress demonstrate that gene regulatory therapy using zinc finger protein transcription factors (ZFP-TF) enables sustained reduction of Tau protein in the brain when administered to a preclinical mouse model of Tau disease. Alzheimer’s, one of the most studied tauopathies. One-time intravenous or intracranial administration of tau-targeted ZFP-TF decreased tau levels by 50-80% at 11 months, the longest time point studied. Zinc finger technology was developed by Sangamo Therapeutics and has now been applied by researchers to reduce the Tau protein in the adult brain, and 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 DZNE in Berlin, the results of the study, carried out in adult mice, indicate that nerve cells appear to be protected against the early toxic effects of amyloid-beta si Tau was reduced by the Zinc finger protein targeted by Tau: “Under certain conditions, such as Alzheimer’s disease, Tau proteins can act as a cellular toxin. Thus, there is a continuous effort to reduce their amount in the brain, ”explains Wegmann. Nerve cell damage first occurs near amyloid plaques, which are, next to Tau, the other type of protein buildup in Alzheimer’s brains.

Wegmann and his colleagues were now able to avoid 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 lasting reduction in Tau production, and thus significantly reduce the toxic effects of plaques,” explains Wegmann. It is also important to note that the long-lasting reduction in Tau did not cause obvious side effects or changes in tissue structure in the brains of the treated mice.

In this publication, we demonstrate that ZFP-TF can reduce Tau mRNA and proteins in neurons both acutely and in the long term in the adult brain. With this, we can achieve a lasting effect on a single injection of therapeutic adeno-associated viruses, without 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 designed to bind very specifically to unique genetic sequences in the cell and reduce or silence their expression. In this work, they were programmed to bind precisely to the sequences of the genetic code of 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 50-80% throughout the brain. Unlike gene-editing approaches, which cut or modify DNA itself, ZFP-TF induce long-term changes in Tau expression without altering the genetic material of cells in the process.

Nerve cells do not naturally produce zinc finger protein, but are designed to do so with a biotechnological technique – by introducing the blueprint of this substance into the cells via an engineered virus. These AAVs cannot multiply or spread, and instead serve as a useful delivery mechanism for ZFP-TF to reach its destination in the brain. The cell’s natural machinery then continuously produces 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 Tau protein in the long term.

“These convincing results published in Scientific progress demonstrate the potential of our highly specific and efficient zinc finger protein transcription factor technology for the treatment of neurological diseases, ”said Bryan Zeitler, director of gene regulation at Sangamo. . This publication represents the promise of Sangamo’s zinc finger protein transcription factor approach to potentially provide a one-time treatment to slow or arrest disease progression. “

The results serve as a basis for further development of the technology and for clinical research in humans. Pharmaceutical company Biogen has entered into a global collaboration agreement with Sangamo to develop gene regulatory therapies based on this approach and the companies are moving towards the clinic.