Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two of the costliest and most devastating neurodegenerative diseases. An estimated 16,000 Americans are affected by ALS, while up to 30,000 suffer from FTD, although these are likely to be underestimates. Research in recent decades has shown that FTD has significant clinical, pathological, and genetic overlap with ALS, and the two are now considered to be on the same disease spectrum. Up to 50% of ALS patients experience cognitive impairment, and up to 15% develop FTD symptoms. ALS/FTD and the morbidity and impairments they cause are accompanied by significant medical, societal, and financial burdens. Total per patient costs are estimated at $70,000 annually for ALS patients and $120,000 annually for FTD patients. Currently, effective diagnostics and treatments for these diseases are lacking, and newer therapies have translated poorly to humans, despite showing great promise in existing in vitro and animal models. A major challenge in the development and testing of new therapies is the lack of models that accurately reflect the underlying pathophysiology. Like all neurodegenerative diseases, animal models for ALS and FTD are hindered by the short lifespans of most animals, which may not allow for adequate disease progression. Differences in the genomes, development, and physiology of human and animal brains are additional complicating factors. Accurate models of these diseases are needed to advance the development of novel biomarkers, diagnostics, and therapeutics. To address this need, SynaptiCure is developing a novel patient-derived 3D platform for high-fidelity modeling and screening of TDP-43 proteinopathy and associated biomarkers for ALS and FTD. SynaptiCure’s innovative mAssembloids platform will provide a new, systematic approach for creating 3D mature brain organoids that more closely reflect disease states relevant to ALS and FTD, including matched extracellular features not seen in any other existing models. In prior work, SynaptiCure was able to form mAssembloids from differentiated human astrocytes and cortical-like neurons in defined numbers and ratios. mAssembloids provide a 3D environment that contains mature astrocytes very similar to those in the healthy human brain, as well as recapitulating key features of ALS such as aging-related disease pathology never before reported in vitro. For this Direct to Phase II project, SynaptiCure proposes to use the mAssembloid platform to develop model systems for several different subtypes of ALS and FTD. Specific Aims of this project are as follows: 1) Generate and validate mAssembloids for genetic models of FTD, ALS, and FTD/ALS; 2) Generate and validate mAssembloids for C9ORF72-associated ALS/FTD; and 3) Generate and validate mAssembloids for sporadic ALS/FTD. It is anticipated that this work will enable the development of superior models and biomarkers that will pave the way for improvements in R&D, patient stratification, and the development of new diagnostic, prognostic, and therapeutic approaches.

Narrative Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating neurogenerative diseases that currently lack effective diagnostics and treatments. A major challenge in the development and testing of novel approaches for ALS and FTD is the lack of models that accurately reflect the underlying pathophysiology of these diseases. SynaptiCure is developing a novel 3D organoid-based platform of differentiated human brain cells, called “mAssembloids” (mature cell type assembloids) for the modeling of ALS and FTD, providing inroads to the development of new tools to ultimately improve patient care.