Phase of Development: Lead Optimization

Mechanism of Action: Tau Proteostasis, Propagation and Clearance

Compound Type/Modality: Antibody/Biologic

Development of tau lowering intrabodies

Sally Temple, PhD

Neural Stem Cell Institute, Rensselaer, New York
Scientific Director and Co-Founder


Tauopathies are characterized by the deposition of insoluble tau protein in neurons and glia with subsequent loss of brain cells and cognitive and health decline. Tau pathology spreads from cell to cell, and several therapies in development focus on halting extracellular secretion and subsequent propagation of abnormal tau protein. However, these methods do not prevent the intracellular accumulation and aggregation of tau, which is itself toxic, and is also upstream from pathogenic cell- to -cell transfer.  The goal of this drug discovery proposal is to develop therapeutic agents that prevent tau protein accumulation inside cells, thus preventing cell death and preventing pathogenic tau spread. Our approach is to use novel antibody-based reagents that act inside cells, and hence are termed ‘intrabodies’.

Executive Summary:

To achieve specificity of tau binding, our approach uses engineered antibodies. Single-chain variable fragments (scFv) are recombinant antibody fragments that can be expressed intracellularly as intrabodies. They exhibit many of the advantages of conventional antibodies, including high specificity and affinity for target epitopes, but lack the Fc domain that is responsible for mediating inflammatory reactions.  Intrabodies can be selected, engineered, and delivered as genes, making them powerful tools to target pathogenic proteins. As a postdoc in the Messer lab, which pioneered the use of engineered antibody fragments against neurodegenerative disease proteins, Dr. Butler developed bifunctional intrabodies that targeted mutant huntingtin protein and α-synuclein to the proteasome for degradation. Using recombinant technologies, we have developed a series of novel bifunctional intrabody reagents that act inside cells with dual action: they specifically bind tau and prevent its aggregation, and they specifically target tau to the proteasome. This is accomplished by a novel approach: fusing the intrabody to the ornithine decarboxylase (ODC) PEST degron which facilitates intrabody and bound tau degradation through ubiquitin-independent proteolysis. In the proposed studies we will test the safety and efficacy of these tau lowering intrabodies in patient derived human induced pluripotent stem cell models of brain cells as well as mouse models of tauopathy that recapitulate human disease phenotypes.

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