Amyotrophic lateral sclerosis (ALS) is a progressive disorder that leads to degeneration of upper and lower motor neurons, muscle atrophy, and ultimately death. The onset of disease is usually between 40 and 60 years of age. In 5% of cases, ALS is caused by a point mutation in the super oxide dismutase 1 gene (SOD1) and is referred to as familial ALS. Motor neuron cell death and paralysis result when this mutation is over expressed in mice and rats (SOD1G93A mutants). This translational research proposal will investigate the efficacy of ex vivo cell therapy targeting skeletal muscles to ameliorate motor neuron death in a rat model of ALS. We will focus on human mesenchymal stem cells (hMSC) derived from bone marrow, which can be isolated from normal donors or patients with ALS, easily expanded to large numbers and modified ex vivo with transgenic genes using viral vectors. We propose to use the hMSC as """"""""Trojan horses"""""""" to deliver key trophic factors postulated to have a role in ALS pathogenesis: glial cell line-derived neurotrophic factor (GDNF), insulin-like growth factor-I (IGF-I), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF). We will also determine the potential benefits of this hMSC based approach compared to a viral vector based approach. Furthermore, we will determine if combined delivery of these growth factors using hMSC has any synergistic effects on motor neuron loss in the SOD1G93A rats.
These aims will provide highly novel insights into effective approaches using cell and growth factor-based treatments for ALS, and may provide the rationale for novel therapeutic strategies for a neurodegenerative disease with no known cure. Our rationale for using human mesenchymal cells in this project is that they represent a safe viable source of cells that could potentially be used in multiple clinical trials. Thus, any results acquired from the use of these cells in animal models of disease will be directly translatable to pre-clinical studies in ALS. The relevance to the NIH mission of improving health becomes extremely high when using human cells. PROJECT NARRATIVE Amyotrophic lateral sclerosis (ALS) is an incurable disease characterized by rapid loss of muscle control and eventual paralysis. The proposed research will contribute new novel information to effective therapies for neurodegenerative diseases, which is relevant to the NIH mission of improving public health.
