Researchers are testing a new gene management approach to treat brain diseases

Researchers at the DZNE (Germany), Massachusetts General Hospital (USA) and the genomic treatment company Sangamo Therapeutics, Inc. conducted a study. testing of a modern gene management approach to treat brain diseases such as Alzheimer’s in laboratory studies. It reduces zinc finger proteins, which specifically bind to the DNA encoding for the protein Tau without modifying it, thus reducing Tau production in the brain and preventing zero damage. The preclinical results, published in the journal Advances in science, which may be the basis for new treatments.

Tau proteins play a key role in the development of some degenerative brain diseases called tauopathies. Tau accumulates and accumulates inside nerve cells, causing destruction of synapses and cell death. The result is progressive dysfunction of mental, motor and psychological abilities.

Results of new research published in the journal Advances in science demonstrated that gene control therapy using zinc finger protein transcription factors (ZFP-TFs) provides stable brain Tau protein reduction when administered to a preclinical mouse model of Alzheimer’s disease, one of the major tauopathies examined. One-time intravenous or intracranial administration of targeted ZFP-TFs reduced tau levels 50 to 80% out to 11 months, the longest time period studied. The zinc branch technology was developed by Sangamo Therapeutics and is now being applied by the researchers to reduce Tau protein in the adult brain. This could be the start of a new generation of treatments for tauopathies such as Alzheimer’s disease and frontotemporal dementia.

Preclinical studies show high efficacy without obvious side effects

According to Susanne Wegmann, head of a research group at the DZNE in Berlin, the results of the study, conducted in adult mice, show that zero cells appear to be protected from the early toxic effects of amyloid- beta if Tau has been reduced by the Tau-targeted Zinc Protein: “Under certain conditions, such as Alzheimer’s disease, Tau proteins can exert the effects of cell toxins. Therefore, there is an ongoing effort to increase their level in the brain. reduction, “Wegmann explains. Nerve cell damage first occurs near amyloid plaques, which, next to Tau, are the other type of protein accumulation found in the brain of Alzheimer’s disease.

Wegmann and colleagues were now able to prevent this by reducing Tau with this approach. “Nerve cells normally secrete Tau proteins. With the help of zinc finger protein technology, we have now been able to achieve a permanent reduction of Tau production, thereby significantly reducing the toxic effects of the blankets, “Wegmann explains. Additional stress is that the long-term Tau reduction did not cause side effects or noticeable 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 both acute and long-term neurons in the adult brain. With this, we can achieve a lasting effect on a single injection of adeno-associated viruses, without any neurotoxic side effects. “

Susanne Wegmann, DZNE Researcher

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

Zinc finger proteins can be engineered to specifically bind to or mimic specific gene sequences within the nucleus and expression. In this work, they were programmed to precisely link sequences in the genetic code for Tau proteins. Thus, the transcription of these sequences, and consequently the production of the Tau protein, is inhibited; as a result, the total amount of Tau decreased 50 to 80% throughout the brain. Unlike gene editing methods, which cut or alter the DNA itself, ZFP-TFs cause long-term changes in Tau expression without altering the genetic material of the cells in the process.

Zero cells do not produce zinc finger proteins naturally, but are produced by a biotechnological method – by introducing a plan for this substance into the cells through a virus. engineered. These AAVs cannot multiply or spread, and instead are a useful delivery method for the ZFP-TF to reach its destination within the brain. The cell’s natural mechanism then releases the ZFP-TF proteins – over a long period of time – to inhibit the Tau gene. In this way, one treatment is likely to be enough to reduce Tau protein in the long run.

“These strong results were published in Advances in science demonstrate the capability of our highly specialized and effective zinc finger protein transcription factor technology for the treatment of neurologic disease, “said Bryan Zeitler, Gene Control Director at Sangamo.” Currently no disease modification mechanisms have been approved. for patients with Alzheimer’s disease or other tauophathies. . This publication represents the promise of a Sangamo zinc finger protein transcription approach to provide one-time treatment to reduce or stop the progression of disease. “

The results will form the basis for further development of the technology and for clinical study in humans. The pharmaceutical company Biogen has a global cooperation agreement with Sangamo to develop gene control therapies based on this approach and the Companies are moving towards the clinic.