Therapeutic Potential of Transplanted human Embryonic Stem Cells Overexpressing Soluble APP in Treating Alzheimer's Disease

Funding Type: 
SEED Grant
Grant Number: 
ICOC Funds Committed: 
Disease Focus: 
Solid Tumor
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Alzheimer disease (AD) afflicts over 5 million elderly Americans and is characterized by deposits of insoluble protein aggregates (amyloid plaques) and neurofibillary tangles) as well as massive neuronal loss in selected regions affecting learning and memory. Stem cell therapy represents a promising strategy for treating the chronic central nervous system (CNS) diseases such as AD by replacing damaged and lost neurons and thus restoring defective cognitive behaviors. Human embryonic neuronal stem cells (hES) transplanted into aged rodent brains are found to differentiate into neuronal cells and significantly improve the cognitive functions of the animals. However, ethical and practical issues remain which compel us to seek alternative strategies. Using a well-characterized human ES line in transplantation is an option which can be greatly enhanced by some potent neurotrophic factors to nourish neurons. In this application, we propose to combine hES with a natural soluble factor, the N-terminal portion of the amyloid precursor protein (sAPP) to create a superior stem cell agent for treating AD. sAPP is present normally in the cerebral spinal fluid (CSF) and its level is found to dramatically decline in AD patients, suggesting that this protein plays a critical role in preventing AD. Indeed, this is the best-characterized natural molecule that displays potent neuroprotective and neurotrophic actions on cultured neurons as well as in CNS cells upon infusion. We thus propose to engineer two human ES lines to secrete sAPP via lentivirus infection and to characterize these established lines for the effects of sAPP on differentiation and migration features of the transduced hES. Subsequently, we will transplant these cells into mouse brains at various ages to optimize a transplantation procedure. Finally, the efficacy of the transplanted hES secreting sAPP will be tested in reducing AD pathology in a selected mouse model that displays massive neuronal death/loss and impaired synaptic function. We hope this study will provide proof-of-concept for an established human ES line with a superior ability to differentiate and to stimulate neighboring neurons to proliferate into new neurons which can be further validated and used in future therapeutics.
Statement of Benefit to California: 
California's population is aging, and as people live longer the incidence of diseases caused by aging increases. This has an enormous economic impact on California, since the caregivers for the elderly are usually their children, who are in the peak of their productive years. Alzheimer's disease (AD), the number one dementia among the elderly, is especially devastating because the disease develops and worsens over a long period of time with no available cure . Stem cell replacement by transplantation represents a promising therapeutic option for treating AD. However, both the ethical and practical issues compel neuroscientists to seek alternative approaches (e.g., using human embryonic stem cell lines, hES lines herein) in addition to using primary human stem cells. The proposed studies to fully characterize and establish well-behaved hES lines with superior ability to replace damaged/lost neurons in AD brains upon transplantation will provide proof-of-concept for future transplantation feasibility in patients. Nationwide, an estimated 5 million Americans have AD. The number of Americans with AD has more than doubled since 1980 and continues to grow at an accelerated rate. California, as a paradise to retirees, accommodates the largest aging population and is estimated to have nearly 1 million people with AD. Additionally California farmers use approximately 250 million pounds of pesticides which is about a quarter of all pesticides used in the entire country. Pesticides have been proven to be neural toxic and linked to higher incidences of Parkinson’s disease and AD. Not to mention curing the disease, finding a treatment that could delay the onset of AD by five years alone could reduce the number of individuals with AD by nearly 50% after 50 years and thus greatly reduce the government’s medicare costs (which are expected to increase 75% from $11 billion in 2005 to $19 billion in 2010 in California).
Progress Report: 
  • Recent studies have shown that mutations in the DNA of adult stem cells can lead to the formation of cancerous rather than normal tissues. However, with the exception of blood, adult stem cells are rare and not readily accessible for isolation or study. Thus, very little is yet known about how these stem cells are hijacked to cause cancer.
  • Our laboratory is studying how mutations in stem cells give rise to Ewing sarcoma. Ewing sarcoma family tumors (ESFT) are highly aggressive tumors that primarily affect children and young adults. ESFT have a specific mutation in their DNA that leads to the creation of a cancer-causing gene called EWS-FLI1. It is our hypothesis that expression of EWS-FLI1 in adult stem cells generates ESFT. In particular, we are interested in a very rare population of adult stem cells called neural crest stem cells (NCSC) and these cells have been the focus of our CIRM-funded grant.
  • We initially proposed that human embryonic stem cells (hESC) could be used to generate NCSC and that these cells would be invaluable tools with which to study the origin of ESFT. In the first year of the grant we successfully achieved this goal and the work has been published. In the second year of the grant we have studied the consequences of activating the EWS-FLI1 on these cells. Importantly, our work shows that NCSC that express EWS-FLI1 do not differentiate normally. Instead they acquire properties of cancer stem cells. Thus, we propose that ESFT arise from NCSC that acquire a genetic mutation that prevents them from developing normally. These abnormal stem cells then go on to develop into full blown tumors.
  • By creating novel stem cell models to study the origin of ESFT we are gaining new insights into how these tumors arise in children. These insights will ultimately aid in the development of more effective therapies that can be designed to destroy abnormal cancer-causing stem cells whilst sparing normal stem cells.

© 2013 California Institute for Regenerative Medicine