Early Translational I
ICOC Funds Committed:
Novel applications for Stem Cell Therapy have been proposed for a broad range of congenital and acquired pathology. The Central Nervous System (CNS) represents a key target for stem cell therapy. Malignant brain and spinal cord tumors remain a leading cause of morbidity and mortality for children and adults. Pediatric brain tumors are second only to leukemia as the most common malignancy of childhood and now represent the leading cause of cancer-related death in children. Accumulating data documents permanent functional disability exhibited by the few fortunate survivors. Amyotrophic Lateral Sclerosis (ALS) (Lou Gehrig’s disease, currently affecting Stephen Hawkins) is a progressive and usually fatal, neurodegenerative disease ultimately resulting from the loss of motor neurons. This leads to progressive muscle weakness and atrophy throughout the body. ALS is one of the most common neuromuscular diseases worldwide, affecting people of all races and ethnic backgrounds, with an incidence of approximately 2 per 100,000 annually. New approaches to the treatment of brain tumors and ALS are desperately needed. A universal platform is needed for realistic, rapid and cost-effective pre-clinical development and testing for human stem cell therapies aimed at specific diseases, such as brain tumors and ALS. The current dilemma of stem cell research arises from attempts to extrapolate results from two disparate techniques. Classically, stem cell development and survival has been solely characterized by describing the fate of dissociated cells grown on highly artificial plastic tissue culture plates. The artifactual nature of this completely foreign tissue culture system with the resultant conflicting results is becoming well recognized, as evidenced by confusing and contradictory results reported by different researchers. Pre-clinical testing of stem cell therapies has classically been evaluated by transplanting stem cell populations into animal disease models to observe for clinical improvement. This essentially represents a process in which stem cells are introduced into a “black box” with the hope of observing some desirable outcome exhibited by the transplanted animal. Here, we propose a universal hybrid platform, which allows for the tracking of stem cell fate after transplantation of these stem cell populations into small slices of brain or spinal cord, replicating human brain tumors and ALS, respectively. Finally, the fate of the patient’s own stem cells will be characterized when reintroduced into their own brain tumor containing brain slices. Through the application of the systematic stem cell investigation paradigm proposed in this application, it is hoped that more reliable pre-clinical assessment of stem cell fate and subsequent biological outcome will translate into improved predictability enabling more rapid development of efficacious, disease-specific stem cell clinical therapies.
Statement of Benefit to California:
Malignant brain and spinal cord tumors remain a leading cause of morbidity and mortality for children and adults including California. Pediatric brain tumors are second only to leukemia as the most common malignancy of childhood and now represent the leading cause of cancer-related death in children. The prognosis for malignant brain tumors remains dismal, best appreciated in poor long-term survival statistics. Accumulating data document permanent functional disability exhibited by the fortunate survivors. The costs for the patient and family cannot be overestimated. Overall estimates of the incidence of brain cancers in the United States show that about 20,000 will be diagnosed annually with about 2500 in California. The economic costs are high. Repeated use of physician, inpatient, outpatient and laboratory services as well as lost future earnings and occurrence of secondary diseases cost Californians of more than 1.5 billion dollars annually. Fundamentally new approaches to the treatment of brain tumors are desperately needed. The objectives of this proposal focus upon utilizing a refined biological model to allow for the direct study of in situ behaviors of stem cell (neural stem cells, embryonic stem cells, induced pluripotent stem cells) and cancer stem cell populations within brain and spinal cord microenvironments with the ultimate goal being improved therapeutic applications.