Modeling Human Disease Using Pluripotent Stem Cells

Modeling familial dysautonomia and other NC-related disorders

Disease Modeling

Familial dysautonomia (FD) is a rare but fatal disorder primarily affecting the peripheral nervous system. We have demonstrated that iPSC technology represents an excellent model of the disease in a dish to study mechanism of disease and to identify and validate promising therapeutic compounds for use in FD patients. Current studies are aimed at understanding variability in disease manifestation among patients and the identification of compounds in our iPSC model to treat later stages of the disease. Other iPSC-based models affecting neural crest lineages include Schwann cell and melanocyte-related disorders, including our effort to model human melanoma in pluripotent stem cells.

Modeling herpes simplex encephalitis and neurodevelopmental disorders

In a multilab collaboration, we have developed methods to model primary herpes simplex encephalitis (HSE) using iPSC cell technology. Those studies have revealed that mutations in a specific pathway (TLR-3 signaling) lead to an autonomous defect of innate immunity in iPSC-derived neurons. The goal of these studies is to further define cellular mechanisms of disease and to model other forms of HSE. Other neurodevelopmental disorders of interest in the lab include autism-spectrum disorders and schizophrenia.

Modeling Parkinson’s disease and other age-related disorders

We have a long-standing interest in modeling Parkinson’s disease (PD) using human iPSC and ESC-derived dopamine neurons.

An important asset is our ability to derive and purify midbrain dopamine neurons, and we are further refining those strategies toward isolating subtypes of dopamine neurons with different vulnerability to the disease. Having developed iPSC lines to many genetic forms of PD, we are interested in shared and distinct mechanisms of disease and whether those mechanisms apply to sporadic disease. We are particularly focused on improving the iPSC-based tools for modeling late-onset disorders such as Parkinson’s disease using state-of-the-art genetic tools for gene repair, cell purification, and manipulation of cell maturation and age. The ability to induce age-like features in PD-iPSC-derived dopamine nerve cells has yielded late-stage disease phenotypes not commonly observed in standard PD-iPSC models.