GABAergic Interneuron Progenitors Derived from Isogenic, ApoE-Corrected Human Induced Pluripotent Stem Cells (iPSCs) for Treatment of ApoE4-Positive Alzheimer's Disease (AD)

Funding Type: 
Early Translational IV
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting over 480,000 individuals in California alone—more than in any other US state—and over 5.4 million individuals in the United States. AD causes the loss of brain cells, or neurons, in brain regions controlling learning and memory. The mechanisms that cause AD are complex, with multiple individual genes and proteins involved. One of these is apoE—a protein essential for the health and repair of neurons. In humans, there are three forms of apoE (apoE2, apoE3, apoE4), and one, apoE4, is the single biggest genetic risk factor for AD.

Because of its complexity, AD presents unique challenges for developing traditional therapies. Induced pluripotent stem cells (iPSCs) generated from skin cells provide a way to replace the neurons that are lost in AD, and pave a new path towards effective therapies. However, current iPSC-based therapeutic approaches for AD do not consider apoE4's impact, which could lead to clinical failure.

We found that apoE4 causes the loss of a selective subpopulation of neurons in the region of the brain important for learning and memory, and that loss of these neurons correlates with the severity of learning and memory deficits in mice. We propose to develop and optimize conditions to generate these lost neurons in a culture dish using iPSCs from AD patients for transplantation studies. Importantly, we will correct patient iPSCs that carry apoE4 to the protective apoE3 or apoE2 form.

Statement of Benefit to California: 

Alzheimer's disease (AD) is the leading cause of dementia and is the fastest growing form of cognitive impairment in California. Currently, there are over 480,000 AD patients in California—more than in any other US state—costing over $20 billion USD in healthcare and lost productivity in 2012 alone.

This research project focuses on developing patient-specific cell-replacement therapies for AD. We will generate multiple human induced pluripotent stem cell (iPSC) lines in which the AD-causing apoE4 gene is corrected to the protective apoE3 or apoE2 form. Successful completion of this research could foster the development of new technologies that could contribute to the California biotechnology industry. For example, these cell lines could be valuable for biotechnology companies and researchers who are screening for drugs targeting AD. Furthermore, the knowledge that will be gained through the proposed studies should also be helpful for biomedical researchers to develop beneficial therapies beyond what is currently available. As many neurodegenerative diseases share pathological features with AD, including subtype-specific neuron loss, this project could also provide proof-of-principle that cell replacement is an effective approach for treating other neurodegenerative disorders that burden Californians. Finally, this research could help to improve the health of Californians and reduce the adverse impact of AD, thereby increasing productivity and enhancing quality of life.