Advancing a Human Stem Cell-Based Platform to Support Discovery of Tauopathy Therapeutics

Rationale:

It is critical for the field that a diverse set of molecular targets and mechanisms be explored beyond the current set that is being investigated. This includes targets that might prevent the expression of Tau through transcriptional regulation, novel targets that regulate Tau misfolding and proteostasis or are involved in its spread and uptake, and other cellular processes emerging as affected by aberrant Tau, including mitochondrial function, DNA damage, transcriptional regulation, and synaptic activity to name a few. Having modulators of these molecular mechanisms systematically tested side-by-side allows the direct comparison of the relative degree of efficacy and a more detailed understanding of the cellular consequences with respect to the desired outcome and undesired effect. While heterologous overexpression systems may be adequate in certain cases, the nature of the diversity of Tau species and the nature of disease-associated proteostasis function makes it critical to examine these mechanisms in systems as physiologically relevant as possible. One way to achieve this objective is to leverage the intellectually rich environment of the Tau Consortium and expand on-going collaborative efforts with a growing number of groups to test specific targets and small molecules side-by-side in our panel of human tauopathy neuron assays though a combination of: i) open nomination of targets/small-molecule probes to test; and ii) hands-on training for investigators.

Drug Discovery Program Status:

Novel assays for aspects of tau proteostasis are being developed and being applied to emerging targets and to support probe and drug discovery programs in the Tau Consortium.

Executive Summary:

There is a critical need to develop innovative therapeutic strategies for the treatment of neurodegenerative disorders in general and tauopathies in particular where aberrant tau is known to play a causal role in disease pathogenesis. We and others have sought to advance a platform for ‘humanizing’ the validation of novel therapeutic targets and discovery of small-molecule probes targeting pathways implicated in tauopathy and neurodegeneration in general. This modular platform leverages advances in the field of human stem cell biology that now allow for the screening of small-molecule probes in tauopathy patient-derived neurons in a high-throughput format. Toward this end, using tauopathy patient-derived iPSC ex vivo models, and expandable neural progenitor cell (NPC) lines derived from them, the overarching goal of this project is to: (Aim 1) implement mechanisms to facilitate screening in human tauopathy models by Tau Consortium members; and (Aim 2) expand the panel of tauopathy iPSC models and assays available for routine small-molecule screening.