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2020 Tau Pipeline Enabling Program (T-PEP)

Safe and effective delivery of MSUT2 siRNA for treatment of tauopathy

Could a new drug delivery approach that blocks the activity of a novel gene be effectively used to tackle tau-related brain diseases?

Jeff Friedman, M.D., Ph.D.
DTx Pharma, LLC
San Diego, 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, Progressive Supranuclear Palsy and over 20 other brain diseases, the shape of tau protein becomes modified or “misfolded” and this could contribute to tau clumps and tangles (a hallmark of these diseases) and subsequent nerve cell damage. 

Recent studies by Dr. Brian Kraemer at the University of Washington and the VA Puget Sound Medical System have shown that removing a gene called MSUT2 lowers modified tau levels and possibly reduces nerve cell damage in the brains of mice that are genetically engineered to have abnormal tau in their brains. Based on the Kraemer lab’s findings, Dr. Jeff Friedman and colleagues at DTx pharma propose to use drug delivery technology developed at DTx to target the MSUT2 gene to test this novel potential therapeutic target

Research Plan

In this study, Dr. Friedman and colleagues will use molecules that target MSUT2 to reduce accumulation of modified tau in the brain. Using a novel drug delivery approach developed by Dr. Friedman’s team, these molecules targeting MSUT2 will be administered to cells in the laboratory dish as well as cognitively unimpaired  mice. The researchers will use these experiments to determine the most effective molecules that are able to block MSUT2 in the brain.

As a final step, Dr. Kraemer’s group will administer the most promising candidate compounds to the genetically engineered Alzheimer’s-like mice. The researchers will measure tau tangles and inflammation in the animals’ brains to understand which candidate might be most effective in protecting these mice from brain damage.


If successful, the study could lead to a potential therapeutic target to prevent or slow tau tangles from forming in the brain during Alzheimer’s and other brain diseases. It may also help validate a novel drug-delivery approach that could be used to administer other therapeutic molecules.

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