A genetic engineering strategy has been utilized to reduce levels of tau protein in an animal model of Alzheimer’s disease, say investigators at Massachusetts General Hospital (MGH) and Sangamo Therapeutics Inc. The results could lead to a potentially promising treatment for patients with this devastating illness.
The strategy, as described in the study1, 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.
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. This suggests a plan forward to try to help patients,
said senior author Bradley Hyman, MD, Ph.D., who directs the Alzheimer’s disease research unit at the MassGeneral Institute for Neurodegenerative Disease.
Reduced Tau Levels
The therapy was designed to target and silence the expression of the gene that codes for tau, a key protein that accumulates and becomes tangled in the brain during the development of Alzheimer’s.
Mice with Alzheimer’s disease got a single injection of the treatment — which employed a harmless adeno-associated 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.
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. 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,
The study was supported by Sangamo Therapeutics. Massachusetts General Hospital and the German Center for Neurodegenerative Diseases (DZNE) of the Helmholtz Foundation, the JPB Foundation, and by NIA training grants to the Division of Medical Sciences at Harvard University.
Susanne Wegmann et al. Persistent repression of tau in the brain using engineered zinc finger protein transcription factors. Science Advances 19 Mar 2021: Vol. 7, no. 12, eabe1611 DOI: 10.1126/sciadv.abe1611 ↩︎