Phase of Development: Hit to Lead

Mechanism of Action: Tau Proteostasis, Propagation and Clearance

Compound Type/Modality: Vaccine

Active Vaccine for Tauopathy

Marc Diamond, MD

Professor, UT Southwestern Medical Center (Dallas, TX)

Public abstract:

We have learned that tau causes neurodegeneration by adopting a three-dimensional structure that is distinct from that found in its normal state. Additionally, we have developed sensitive methods to detect these structures. This knowledge is allowing us to design new vaccines that will stimulate the immune system to attack pathological forms as they move through the brain. Pathological forms of tau are distinguished by conformational changes that expose different portions of the protein to attack by the immune system. Consequently, we have developed panels of antibodies that recognize distinct regions of tau, and different conformational states. These antisera are used to immune-precipitate total tau and pathological tau seeding activity from P301S mouse tauopathy brain. We are determining which regions of tau are best targeted to specifically interact with pathological (i.e. seed-competent) and not inert forms. It is expected that vaccines that preferentially target pathological tau will be most effective. Vaccines that give rise to antisera that work best will be tested in the P301S tauopathy mice. This work is a proof-of-concept to test whether a structure-based in vitro antibody assay can predict efficacy in vivo. If successful, it will enable us to identify vaccines that work best against specific human tauopathy brains, and it will enter clinical trials relatively rapidly.

Lay description:

The goal of this project is to use biochemical and structural knowledge of the tau protein to develop new therapies for tauopathy. Tau causes dementia in a variety of syndromes. Prior Tau Consortium support has helped us understand the diversity of structures tau forms when it self-associates into toxic assemblies. We are now using this knowledge to teach the immune system to recognize these structures through design of specific vaccines, and thereby prevent disease progression.

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