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Designing the first structure-based

tau aggregation inhibitors

Tauopathies are diseases caused by tau aggregation

The tau protein, an important contributor to cellular function within the brain, aggregates to form fibrils in a class of neurodegenerative diseases known as tauopathies.  These include Alzheimer’s disease (AD), non-AD dementias such as frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP), and chronic-traumatic encephalopathy (CTE), which is notable for being the result of head trauma.  When tau aggregates, transport and other cellular processes within cells in the brain are disrupted. This leads to the breakdown of connections between these cells that are critical for function, leading to cell death and atrophy of the brain.

Tauopathies afflict millions of people. AD is the most common tauopathy, affecting 5.3 million Americans and 35 million people worldwide.  It is the 6th leading cause of death in the US, but it is the only cause of death in the top 10 for which there are no treatments that prevent, cure, or slow 

the disease. There is a great societal need to fill this void. 

Designing novel tau aggregation inhibitors (TAIs)

David Eisenberg and colleagues at UCLA have reported the atomic structures of aggregated regions of tau, and have shown that their aggregation can be stopped with inhibitors designed using these structural models.   At ADRx, we have used our ADvantage drug discovery platform to design and evolve more highly potent TAIs.  Peptide-based TAIs have been delivered by a viral vector into the brains of mice that model tauopathies and have produced a robust reduction in tau aggregation. ADRx has leveraged these peptide TAIs to develop unique assays to find small molecules capable of achieving the same effect. These small molecule TAIs will circumvent the challenges in delivery of large molecule inhibitors into the brain.  ADRx has exclusively licensed intellectual property from UCLA that protects the structure-based approach to the design of tau aggregation inhibitors and has additionally filed two new patent applications covering novel TAIs.