In vivo synaptic function in human neurogenetic disease

Funding Type: 
Basic Biology III
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

Pluripotent stem cells have two remarkable properties: they can divide seemingly endlessly and therefore produce large quantities of identical daughter cells, and they can also be induced to mature into virtually any cell type that makes up the human body. They are thus very useful as a source of material for biomedical research and potential medical applications. However, until recently, these cells have been hard to come by. Now, through a relatively simple process, pluripotent stem cells can be produced from virtually any cell type, including skin cells. Because collecting skin cells does not cause a person any harm we can use these to make a wide variety of cell types from individuals with specific diseases. Using this strategy it is therefore possible to take skin cells from an individual with an inherited brain disorder, turn these into brain cells, and use these to study the causes of the patient’s disease in the laboratory without ever having to touch the patient’s brain. The enthusiasm that this remarkable achievement generates, however, is tempered by the fact that finding the right environment to support development of fully functional brain cells grown in a dish in the laboratory has been difficult. In this study we will use the fact that recent studies have shown that pluripotent stem when injected into the brains of very young mice can integrate into host brain tissue and form functional brain cells. Thus we will use the animal’s brain to do what we cannot now do in the lab, make fully functional brain cells from the pluripotent stem cells. By using cells taken from patients with a specific inherited disease of the brain, therefore, we will be able to study proper brain cells and their disease in their natural environment, the brain, and, by doing so, develop new treatments for that disease. For our initial studies, we will begin by looking at the disease Fragile X syndrome, because of its unique properties and because it is the single leading cause of autism.

Statement of Benefit to California: 

The autism spectrum disorders represent the single leading cause of intellectual disability (ID) in children. National annual costs exceed $35 billion, a figure that is expected to rise to $400 billion in the next decade. Although the evidence for a genetic component of ASDs is strong, identification of the gene or genes responsible has been difficult, suggesting that many different genes may play a role. Indeed, several genes have already been identified but most of them, individually, account for only a very small proportion of cases of ASD. Fragile X syndrome, on the other hand, not only represents an identified gene defect that is responsible for the most cases of intellectual disability in boys, about 40% of boys with FXS also have ASD, suggesting a very strong connection between the two IDs. Our studies intend to capitalize on this connection by developing a research method, based on analysis of neurons derived from induced pluripotent stem cells, which can be used to define the mechanisms underlying FXS and that contribute to ASD in this class of patients. If successful, we will be able to extend these studies to other causes of ASDs and provide, based on solid science, new therapeutic targets for this enigmatic class of childhood developmental disorders.