Using NF1 Patient-Derived Induced Pluripotent Stem Cells to Investigate Mechanisms Underlying Cognitive Impairments
Abstract
Neurofibromatosis type 1 (NF1) is a potentially debilitating disorder typified by a predisposition to the formation of tumors in the nervous system and mild to severe neurological impairments. Many, if not most, NF1 patients have problems with attention, learning, and memory to some degree. These cognitive impairments can be among the most devastating and frustrating symptoms for patients and can have a profound effect on quality of life. Despite the gravity of these symptoms, we have very little understanding of how and why mutations in the NF1 gene can cause changes in brain function that lead to impaired cognitive abilities, and even less knowledge about how to treat these symptoms. This is, in part, due to the intrinsic difficulty in treating any disorder associated with cognitive impairments, which is not unique to NF1 patients. Historically, psychiatric and neurological disorders have been extremely challenging to treat because we simply do not have access to live human brains to conduct the kind of controlled experiments that are necessary to investigate underlying mechanisms. Indeed, many of the effective pharmaceutical treatments for psychiatric disorders, including major depression, schizophrenia, bipolar disorder, and ADHD (attention deficit hyperactivity disorder), were discovered through serendipity. We still don t understand how most of these therapies work on a cellular and neural systems level, and there can be severe side effects of exposing the entire brain to drugs that can only partially alleviate the most problematic symptoms. More recent investigations of cell function and disease mechanisms that resulted in new pharmaceutical approaches based on specific biological hypotheses were largely conducted in animal models and have mostly failed when taken to clinical trials in humans. What is desperately needed is an understanding of how specific disorders, or specific symptoms, are related to biological processes in human cells that can be selectively targeted for therapeutic intervention. Perhaps the most significant recent event in the biomedical field to address this need was the Nobel Prize-winning discovery in 2006 that described a method to convert skin cells from adult humans into induced pluripotent stem cells (iPSCs), capable of differentiating into any cell type in the body. This discovery holds the promise to revolutionize our investigation of neurological and psychiatric disease and drug testing because we can now generate an unlimited supply of human brain cells, or neurons, that have the identical genetic makeup as the patients who donated the skin cells. For the first time in history, we can study the development and function of human brain cells that have disease-causing mutations under well-defined conditions. We propose to use this technology to generate iPSCs from skin cells of six NF1 patients and differentiate these iPSCs into specific neuronal cell types that have been suggested to be involved in NF1-related cognitive deficits from studies in animal models. We will then investigate the properties of these NF1-patient derived brain cells at multiple levels compared to cells generated from unaffected individuals. We can determine whether there are any deficits in the types of brain cells we can produce through targeted differentiation, the capacity of these cells to perform requisite neuronal functions of communicating with other brain cells, and the expression level of any gene in these cells. In addition, we will test whether specific drugs that have been shown in animal models of NF1 to affect neuronal differentiation, brain cell function, and learning and memory actually have an effect in human neurons. One of the most pressing concerns in translating animal research to clinical trials is that we often don t know whether a given gene performs the same function or a drug will be as effective in rodents and humans. Our study will directly address the function of NF
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610080
Entities
People
- Hongjun Song
Organizations
- Johns Hopkins University
- United States Army