Summary: Researchers have developed a gene-regulation therapy that markedly lowers tau protein levels in animal models of Alzheimer’s disease after a single administration, with effects that persist for many months.
Source: Mass General
Scientists at Massachusetts General Hospital (MGH), in collaboration with Sangamo Therapeutics Inc., report a promising gene-based approach that substantially reduces tau, a protein that accumulates and forms tangles in the brains of people with Alzheimer’s disease.
The experimental treatment uses engineered zinc finger protein transcription factors (ZFP-TFs), a form of DNA-targeting protein that can be programmed to repress the expression of specific genes. In this study the ZFP-TFs were designed to silence the gene that encodes tau, aiming to lower tau production at its source.
Mice that model Alzheimer’s disease received a single administration of the therapy. The treatment was delivered either directly into the hippocampus, a brain region essential for memory, or intravenously to enable more widespread delivery across the brain. The ZFP-TFs were packaged in an adeno-associated virus (AAV) vector, a commonly studied carrier for gene delivery that is considered nonpathogenic.
Across the study period, treatment with AAV-delivered ZFP-TFs reduced tau messenger RNA and protein levels by roughly 50% to 80%, with these reductions maintained out to the longest time point examined, 11 months. Beyond lowering tau, the therapy also reversed some neurodegenerative changes in the animals’ brains, including damage linked to amyloid plaques in a mouse model that combines amyloid and tau pathology.
“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,” says Bradley Hyman, MD, PhD, director of the Alzheimer’s disease research unit at the MassGeneral Institute for Neurodegenerative Disease and the senior author on the study. He highlights the potential of a single-treatment strategy to produce long-lasting effects.
A major advantage of this approach is its relative simplicity: a one-time administration that achieves durable gene repression. When delivered intravenously, the treatment has the potential to reach broad regions of the brain, while localized hippocampal injection allows targeted delivery to areas most affected in early Alzheimer’s disease. Although further development, extensive safety testing, and regulatory review would be required before any human application, these preclinical results provide a strong rationale for continued investigation.
Funding: The research was primarily supported by Sangamo under a sponsored research agreement with MGH. Additional funding came from Massachusetts General Hospital, the German Center for Neurodegenerative Diseases (DZNE) of the Helmholtz Foundation, the JPB Foundation, the National Institute on Aging, and the BrightFocus Foundation.
About this genetics and Alzheimer’s disease research news
Source: Mass General
Contact: Michael Morrison – Mass General
Image: The image is in the public domain
Original Research: Open access. Title: “Persistent repression of tau in the brain using engineered zinc finger protein transcription factors” by Bradley Hyman et al., published in Science Advances.
Abstract
Persistent repression of tau in the brain using engineered zinc finger protein transcription factors
Lowering neuronal tau has been shown to increase resilience against β-amyloid and tau-related neurotoxicity in laboratory and animal models. This study presents a translational strategy to reduce expression of the tau gene (MAPT) at the transcriptional level using gene-silencing zinc finger protein transcription factors (ZFP-TFs).
After a single administration of AAV carrying ZFP-TFs, delivered either locally into the hippocampus or intravenously to enable broader brain transduction, the researchers observed selective reductions of tau mRNA and protein by approximately 50% to 80% that persisted for up to 11 months. Sustained lowering was achieved without detectable off-target effects, overt histopathological abnormalities, or adverse molecular changes in the tissue examined. In a mouse model combining amyloid pathology (APP/PS1 line) with tau pathology, tau reduction achieved with AAV ZFP-TFs rescued neuronal damage observed around amyloid plaques.
The study concludes that AAV-delivered ZFP-TFs provide a highly specific, durable, and controllable method to knock down endogenous tau, supporting further development of this approach as a potential therapy for tau-related human brain diseases.