Identifying Drugs for Alzheimer's Disease with Human Neurons Made From Human IPS cells

Funding Type: 
Early Translational III
Grant Number: 
Award Value: 
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
Public Abstract: 

We propose to discover new drug candidates for Alzheimer’s Disease (AD), which is common, fatal, and for which no effective disease-modifying drugs are available. Because no effective AD treatment is available or imminent, we propose to discover novel candidates by screening purified human brain cells made from human reprogrammed stem cells (human IPS cells or hIPSC) from patients that have rare and aggressive hereditary forms of AD. We have already discovered that such human brain cells exhibit an unique biochemical behavior that indicates early development of AD in a dish. Thus, we hope to find new drugs by using the new tools of human stem cells that were previously unavailable. We think that human brain cells in a dish will succeed where animal models and other types of cells have thus far failed.

Statement of Benefit to California: 

Alzheimer’s Disease (AD) is a fatal neurodegenerative disease that afflicts millions of Californians. The emotional and financial impact on families and on the state healthcare budget is enormous. This project seeks to find new drugs to treat this terrible disease. If we are successful our work in the long-term may help diminish the social and familial cost of AD, and lead to establishment of new businesses in California using our approaches to drug discovery for AD.

Progress Report: 

We have made steady and significant progress in developing a way to use human reprogrammed stem cells to develop drugs for Alzheimer's disease. In the more recent project term we have further refined our key assay, and generated sufficient cells to enable screening of 50,000 different chemical candidates that might reveal potential drugs for this terrible disease. With a little bit of additional refinement, we will be able to begin our search in earnest in collaboration with the Sanford-Burnham Prebys Screening Center.

During the past year we completed screening of our Alzheimers “disease in a dish” cultured stem cell lines for response of a critical measure of Alzheimers disease in a dish to FDA approved drugs and other potentially promising drug like compounds. We found several reproducible and interesting categories of potential drugs some of which are already in common use in human patients and therefore might be readily available to the Alzheimer's disease population. We are conducting more careful analyses of these drugs for their mechanism and behavior in human neurons with different types of Alzheimer like behavior and we are beginning to test whether all human variants behave the same way as preparation for potential clinical trials. We are also initiating analysis of new chemical entities for possible modification to improve potency.

The overall goal for the three years of our grant support has been to develop viable candidate drugs to reduce the known pathologies of Alzheimer Disease (AD). Previous years, we have been able to validate a robust hIPSC-screening assay based on these pathologies to uncover some interesting and reproducible potential drugs, including some drugs currently FDA approved and in common use for other human diseases.
In the past year of this grant, we have successfully screened optimized versions of these potential drugs to determine any increases in treatment potency and have identified several promising new drugs. In the course of our studies, we have discovered a novel kinase-driven mechanism, leading to increases in AD tangles. Many of our newly characterized drug candidates regulate similar pathways in other systems by blocking specific kinase actions. Thus we have opened the door to future large-scale screens of both known and unknown signaling blockers, for which large chemical small molecule libraries exist.
Between optimizing our screening assay and waiting for compounds, we still have significant work to complete to meet our prime objective. In the near future, we plan to continue careful analyses of our identified drugs for both mechanism of action and treatment efficacy in AD variant cell types, prior to initiating controlled preclinical mouse model studies. Our overall goal of identifying promising small molecule treatments for this devastating disease remains undiminished.