Embryonic stem cell-derived neural stem cells for brain tumor and ALS therapy.

Funding Type: 
Comprehensive Grant
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

Glioblastoma is the most common and aggressive brain tumor. Despite surgery, radiation and chemotherapy, the median survival remains approximately 12 months. ALS is a neurodegenerative disease that attacks motor neurons and causes degeneration of nerves of the brain and spinal cord. The diagnosis of ALS leads to unrelenting progressive weakness leading to inability to breath. This project proposes fundamental scientific and clinical goals that are intimately tied: to understand the biology of neural stem cells (NSCs) derived from embryonic stem cells and to manipulate these functions for therapy.

The limitation of current therapies for glioblastoma and ALS stems from their inablility to target infiltrating tumor cells and degenerating motor neurons within the spinal cord, respectively. However, the obstacles to effective therapy match the known biological properties of neural stem cells (NSCs). NSCs display a dramatic property of attraction towards areas of both tumors and neurodegeneration in the adult central nervous system.

We have demonstrated the safety and usefulness fetal NSCs as delivery vehicles as a means of delivering agents to kill infiltrating brain tumor cells and have demonstrated a mechanism of how they are attracted to glioblastoma cells. We also described a rapid culture process whereby neural stem cells can be obtained from bone marrow cells. We have also demonstrated the ability of NSCs to prevent the progression of ALS in a mouse model of the human disease. We have demonstrated functional improvement and increased survival in SOD1 transgenic mice treated with intraspinal injections of fetal neural stem cells.

These findings – taken together with the desperate state-of-affairs in glioblastoma and ALS therapy -- underscore the importance of research that might accelerate the translation of NSC-based adjuvant treatment strategies. This strategy has garnered attention, in part, because of the pioneering efforts and seminal reports from the investigators on this proposal who now hope to advance it rationally towards clinical translation.

More recently, our collaborators have derived NSCs from pluripotent embryonic stem cells (ESCs), termed “ESC-derived NSCs” using a human feeder layer. Culturing without an animal feeder layer enables the clinical development of these cells. The use of NSCs derived from embryonic stem cells have the advantage of being well-characterized and readily available in limitless quantities for the earliest phases of a disease or insult.
Starting from this point of departure, we will:

AIM 1: Determine the attraction toward gliomas and areas of neurodegeneration of hNSCs derived from ESCs.
AIM 2: Determine efficacy & safety of hNSCs derived from ESCs in targeting tumor-killing agents to human gliomas in mice.
AIM 3: Determine efficacy & safety hESC-derived hNSCs in treating motor neuron degeneration in the SOD1 mouse model of ALS.

Statement of Benefit to California: 

This research will benefit California and its citizens by exploiting the powerful properties of embryonic stem cells to be made into brain and spinal cord cells to treat two very devastating neurologic disorders- glioblastoma (brain tumors) and ALS (Lou Gehrig's disease). This proposal addresses the principle aspiration of CIRM: 'to use stem cells to cure a variety of diseases.' Our goal and that of CIRM is to advance therapies to early stage clinical trials. This project will have an impact on five of the ten listed goals of CIRM's Scientific Strategic Plan: Goal I, CIRM grantees will have six therapies based on stem cell research in pre-clinical development -- We will advance two novel therapies for two devastating neurological disorders, glioblastoma and ALS. Goal II: CIRM grantees will have developed new methods of making stem cell lines- We are and will continue to develop efficient means of differentiating ESCs to neural progenitor cells. Goal VII, CIRM will have increased the workforce of stem cell researchers in California-We will recruit two full time trainees to work on this grant. Goal IX and X: CIRM will have established effective partnerships in stem cell research between scientific teams in non-profit and commercial centers and between national and international collaborations in stem cell research- This grant proposal forges a strong collaboration between a large clinical and preclinical entity with investigators that have a proven track record in preclinical development and clinical research and basic embryonic stem cell research with a superb basic stem cell research institute with an investigator that has made seminal contributions in the stem cell therapy field. The ESC lines that will be used were developed in xenogen-free medium with a human feeder layer in collaboration with a non-profit component of a large commercial leader in embryonic stem cell development with laboratories in {REDACTED}. The development of stem cell therapies for these devastating neurological disorders would make California the leading state for stem cell therapies, attracting both scientific talent and, in the future, investment for commercialization of these therapies.