Intracellular targeting of Tau-specific single domain antibodies

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The Tau protein is a common pathophysiological player in cancers and neurodegenerative diseases and, overall, an important therapeutic target. Tau is mainly known as a cytosolic microtubule-associated protein that aggregates into filaments leading to neurodegeneration in pathological conditions referred to as tauopathies. In addition to microtubule dynamics, Tau’s physiological roles also include the protection and reparation of DNA following damage in the nucleus. However, Tau re-expression causes resistance to chemo- or radiotherapy during cancer treatment. The primary goal of the proposal NanoTarget is to develop new antibody-based tools for the intracellular targeting of Tau to modulate the protein’s binding to its partners.Within NanoTarget, the French and German project partners will combine their expertise in biological chemistry, structural biology, biochemistry and molecular physiology to generate cell-permeable Tau-specific nanobodies (Nbs) for their biological evaluation in living cells, including neurons. We will enable applications related to cancer and neurodegeneration, thus requiring delivery of the Nbs at a specific location inside the cell, to reach the core of the pathology. We hypothesize that Tau-specific Nbs could prevent Tau self-association inside neurons in a series of related pathologies called tauopathies, which include Alzheimer’s disease. Furthermore, building upon our ability to engineer Nbs for the compartment-specific cellular delivery, we plan to modulate nuclear Tau function. These cell-permeable Tau-specific Nbs will be chemically modified to monitor their location in cells, thus providing new tools for biological and biomedical research. NanoTarget’s ultimate goal is to provide unprecedented Tau-specific nanobody-based modalities with unmet potential as biological research tools and next-generation biopharmaceuticals. NanoTarget will support our research in the highly competitive field of tauopathies but also extend our original advances in the field of cancer. To date, the potential to reach Tau inside the cells with immunologic approaches has hardly been investigated. The intracellular delivery of functional proteins in living cells, which is essential for NanoTarget, is indeed a challenging task in the molecular life sciences, but it could prove extremely powerful for the development of new drugs. Key factors to be addressed in this context include the stability, cell permeability, and pharmacologic potency of the delivered proteins while maintaining their functional properties. The project’s viability to reach this ambitious goal is supported by the applicants’ proven expertise in protein chemistry and in particular cell-permeable Nb engineering, structural biology, cell biology, their solid track record in Tau research, and their previous successful collaborations.