Modeling TSC and Translating for Therapeutics with Human Cerebral Organoids
Abstract
The Rationale, Objective, and Aims: Focus Areas: (1) Gaining a deeper knowledge of tuberous sclerosis complex (TSC) signaling pathways and the cellular consequences of TSC deficiency; (2) improving TSC disease models; and (3) facilitating therapeutics, biomarkers, and clinical trials research. Rationale: TSC is a genetic disorder caused by mutations in either TSC1 or TSC2 genes. TSC affects multiple organ systems, with prominent involvement of the brain, skin, kidneys, and lungs. In addition to the brain lesions, including cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas in TSC patients, neurologic impairment causes the greatest morbidity in TSC. For example, approximately 50% of TSC patients are affected with autism spectrum disorders (ASDs), including a wide range of autistic symptoms overlapping with that in idiopathic ASD patients. Despite considerable progress in understanding the signaling mechanisms underlying TSC in animal models, the causes the neuropsychiatric manifestations in TSC patients are still poorly understood and effective treatments are still lacking, largely due to the unique properties of the human brain and the difficulty of translating the basic findings in animal models into human therapeutics. For example, although several studies have shown that tuber formation affects the severity of epilepsy in TSC, the correlation of cortical tubers and ASD symptoms is weak and patients without tubers can also have significant developmental deficits, including intellectual disability and autism, suggesting that ASD phenotypes in TSC may be caused by unknown mechanisms rather than cortical tubers. On the other hand, overactive mTOR pathway has been seen in TSC and several mTOR-inhibiting drugs have been approved or are in clinical trials for treating subependymal giant cell astrocytomas and renal angiomyolipomas. However, whether these mTOR-inhibiting drugs could rescue the ASD-related developmental deficits in human brain is unknown. Given the difficulty of cross-species predictive validity, development of a novel human-specific model that can faithfully recapitulate human brain development under normal and pathological conditions is imperative. Since human brain organoids are remarkably similar to human organogenesis in vivo, they provide a unique opportunity to model neurodevelopment in a dish in vitro. Objective: With the overall goal to develop patient-specific induced-pluripotent stem cells (iPSC)-derived 3-D cerebral organoids as a translational model to study the mechanisms underlying developmental deficits of TSC and identify and validate the potential therapeutic targets, our specific goal is to test the hypothesis if TSC mutations act through mTOR pathway to impair neural development and function, and if mTOR-inhibiting drugs or other potential therapeutic compounds could rescue the developmental deficits in TSC. Specific Aims: Aim 1 will determine the cellular impacts of TSC mutations on neural development and evaluate the effect of mTOR-inhibiting drugs in human cerebral organoids. Aim 2 will delineate the cell type specific molecular signatures associated with TSC during brain development with single-cell RNA sequencing. Applicability of the Research: Patient Population(s) That the Work Will Benefit: Successful completion of our work will first benefit patients with TSC in general population and Armed Services. In addition, given the fundamental nature of our discovery, it may also benefit patients suffering from other neuropsychiatric or neurodevelopmental disorders such as autism spectrum disorders and fragile X syndrome. Potential Clinical applications: The potential clinical applications include identifying therapeutic targets for drug development, developing diagnostic methods to monitor neural development and function, using the key readouts of the mechanism as a biomarker for disease status, and screening for drug candidates.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910353
Entities
People
- Zhexing Wen
Organizations
- Emory University
- United States Army