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2020 Tau Pipeline Enabling Program (T-PEP)

Reducing tau burden by targeting its RNA with small molecules

Could the genetic material that provides instructions for making tau be a new potential therapeutic target for frontotemporal dementia and other brain diseases?

Matthew Disney, Ph.D.
The Scripps Research Institute
La Jolla, CA - United States


The brain cell’s nutrient and energy transport system is organized in parallel strands like railroad tracks. These tracks allow nutrients to travel across the cell, delivering key materials to the cells, providing them with energy and keeping them healthy. The tau protein helps keep these tracks straight. However, in Alzheimer’s, frontotemporal dementia (FTD), Parkinson’s disease and over 20 other brain diseases the shape of tau protein becomes modified or “misfolded” and this could contribute to tau tangles (a hallmark of these diseases) and subsequent nerve cell damage. 

The gene that provides instructions for making the tau protein is called microtubule-associated protein tau, or MAPT. Studies show that certain variations in the MAPT gene may increase a person’s risk of developing brain diseases like FTD. When cells activate a gene, they produce a small piece of corresponding genetic material, called ribonucleic acid (RNA). Dr. Disney and colleagues have developed chemical compounds that attach to MAPT RNA and believes that that this approach may prevent cells from using the genetic material (MAPT RNA) to make modified tau.


Research Plan

Dr. Disney’s research team will test their small molecules in a series of biochemical, mouse and human studies. First, they will identify the chemical compound structures that best attach to MAPT RNA. The team will also identify compounds that are effective in preventing the cells from producing modified tau.

The researchers will then advance the most promising molecules to animal and human studies and determine their ability to enter the blood-brain barrier (BBB) - a highly selective barrier that filters large particles from the blood and does not allow them to enter the brain.


If successful, this work could help optimize potentially therapeutic molecules designed to delay or slow production of modified tau in the brain. The results could lead to development of clinical trials testing the molecules’ efficacy in people with FTD, Alzheimer’s and other tau-related brain diseases.

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