3D in vitro model of genetic and sporadic FTD: accelerating novel therapeutic development

Abstract Up to 60,000 Americans suffer from frontotemporal dementia (FTD), a common form of dementia associated with frontotemporal lobar degeneration (FTLD). The associated morbidity and cognitive and physical impairments are accompanied by significant medical, societal, and financial burdens reaching billions of dollars per year in the U.S. Effective diagnostics and treatments are lacking, and newer therapies have translated poorly to humans, despite showing promise in existing in vitro and animal models. Accurate models of FTLD are needed to advance the development of novel biomarkers, diagnostic and prognostic tools, and therapeutics. Brain organoid systems are emerging to model complex human cellular interactions. However, cell types and numbers are difficult to standardize due to reliance on cell lineage specification and the long maturation time within the organoids. To solve this complex problem, Synapticure has developed a novel patient-derived 3D in vitro platform for high-fidelity modeling and screening of pathological phenotypes and biomarkers associated with neurodegenerative diseases. Synapticure’s cortical brain spheroids (CBS) are composed of key cells derived from patient-induced pluripotent stem cells (iPSCs) and are custom assembled into 3D co-cultures, recapitulating disease features not cumulatively seen in any existing in vitro or in vivo model. Synapticure has developed the CBS model for ALS and now, through this Direct to Phase II SBIR, seeks to demonstrate the applicability of the CBS platform to FTD patient-derived iPSCs. This will include developing model systems for different subtypes, genetic and sporadic, of FTD. To evaluate the success of these models, the project team will assay markers of TDP-43 proteinopathy, which contributes to disease in ~45% of FTD cases, as well as tauopathy, which contributes to disease in 40% of FTD cases. This evaluation will include TDP-43 localization, the mis-splicing of transcripts linked to TDP-43 proteinopathy, and tau splicing, expression level and localization. This project will generate and validate CBS for genetic TDP43-FLTD, tau-FLTD, and sporadic FTD. Once validated, this platform will enable the elucidation of novel druggable pathways, screening and validation of disease-specific biomarkers, screening of potential therapies in patient-derived cell models, and better stratification of patient cohorts for clinical trials.