Engineering Conformation-Specific de Novo Therapeutics Targeting PSP and CBD Tau Amyloid Strains

Pipeline Grant

Nikolaos Louros, University of Texas Southwestern Medical Center

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are devastating brain diseases caused by the buildup of abnormal forms of a protein called tau. In healthy cells, tau has important functions, but in these diseases it folds into dense, thread-like structures that spread from cell to cell, leading to the death of brain cells and progressive loss of movement and cognition. Recent advances have revealed that tau can form distinct three-dimensional shapes—or “strains”—in different diseases, explaining why PSP and CBD affect specific brain regions and show unique symptoms.

Current treatments do not stop or slow this process, largely because existing drugs cannot distinguish between the normal and diseased forms of tau. In this project, we will use artificial intelligence (AI) to design new protein-based molecules that can recognize and neutralize the specific harmful tau shapes found in PSP and CBD, without affecting healthy tau. Using advanced computational modeling, we will design and test thousands of candidates and screen them directly against brain tissue samples donated by patients. The most promising candidates will be developed into “degraders” that tag toxic tau for removal by the cell’s natural cleanup machinery.

This research represents an important step toward precision therapies for PSP and CBD—treatments that are tailored to the exact structure of the disease-causing protein. It will also establish a broadly useful platform for designing similar therapies for other neurodegenerative diseases involving abnormal protein aggregation.