Frontotemporal dementia with parkinsonism (FTDP) is a devastating inherited brain disorder that leads to personality changes, cognitive decline, and movement problems. It is caused by an imbalance in two forms of the tau protein, known as 3R and 4R tau. In healthy adult brains, these forms are produced in equal amounts, but in FTDP, too much 4R tau is made, which contributes to harmful clumping of tau and brain cell damage.

This project aims to develop a new therapy using antisense oligonucleotides (ASOs)—short strands of engineered RNA-like molecules—to restore the balance of 3R and 4R tau. These ASOs will specifically target RNA sequences that control how the tau gene (called MAPT) is processed in brain cells. Our recent research discovered new regulatory elements in this RNA code that are essential for maintaining proper tau balance during brain development. By blocking these elements with ASOs, we were able to reduce the harmful 4R tau form in human cells.

We now plan to refine these ASOs and test them in mice that carry the human version of the MAPT gene that carry FTDP-causing mutations, mimicking the disease more closely. These studies will evaluate how well the ASOs work in living animals and whether they can serve as a foundation for further drug development.

If successful, this research could lead to a first-in-class, disease-modifying treatment for FTDP. Because tau pathologies are also involved in other diseases like Alzheimer’s, this approach could eventually benefit a broader range of patients suffering from neurodegenerative tau disorders.