Stem Cell Application for Amyotrophic Lateral Sclerosis: Growth Factor Delivery and Cell Therapy

Abstract

1.1 ALS and the SOD1 rodent models Amyotrophic lateral sclerosis (ALS) is a progressive disorder that leads to degeneration of upper and lower motor neurons, muscular atrophy, and (ultimately) death. A clinical diagnosis of ALS requires signs of progressive degeneration in both upper and lower motor neurons, with no evidence that suggest that the signs can be explained by other disease processes (Brooks et al., 1994, 2000). The incidence rate of the disease is around 2 in 100,000 people (Hirtz et al., 2007). The onset age of sporadic and most familial form of ALS is between 50-60 years, and is generally fatal within 1-5 years of onset (Cleveland & Rothstein, 2001). Riluzile is the only drug that demonstrates a beneficial effect on ALS patients, but only increases survival by a matter of months (Zoccolella et al., 2009). Motor neuron cell death in ALS probably involves multiple pathways. Most ALS cases are sporadic in nature, while ~10% arise from a dominantly inherited trait (familial ALS or FALS) (Brown, 1995). The cause for sporadic ALS remains unclear, while 20% of FALS patients have a point mutation in the cytosolic Cu2+/Zn2+ superoxide dismutase 1 (SOD1) gene (Rosen et al., 1993). Recent reports suggested that other causes of FALS also include mutations in TDP-43 (the 43-KDa TAR DNA binding protein) and FUS (Fused in sarcoma/translocated in liposarcoma) genes (Ticozzi et al, 2011). From various lines of transgenic mice, we can observe that motor neuron disease is developed in mutants with elevated SOD1 levels (ex. hSOD1-G93A line), while no symptoms are observed in SOD1 knockout mice. The combined effect shows that SOD1 acts through a toxic gain of function rather than loss of dismutase activity (Julien et al., 2001). Both mouse and rat models overexpressing SOD1 genes show similar disease phenotypes and disease progression to those observed in human ALS patients (Gurney, 1994; Nagai et al., 2001; Howland et al., 2002). The mechanism underlying motor neuron death in ALS is still unknown. However, SOD1 mutant induces non-cell-autonomous motor neuron killing by an unknown gain of toxicity, which means the gain of toxicity arises from damage to cells other than motor neurons (Boillee et al., 2006a). Multiple mechanisms account for the selective vulnerability of motor neurons including protein misfolding, mitochondrial dysfunction, oxidative damage, defective axonal transport, excitoxicity, insufficient growth factor signaling, and inflammation (Boillee et al., 2006a). Of course there are a lot of shortcomings for using