**8. References**

428 Amyotrophic Lateral Sclerosis

Chron disease and ulcerative colitis), infections (fungal infections such as histoplasmosis, coccidioidomycosis, blastomycosis and tuberculosis), congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site

Clinical trials examining the effects of TNF- inhibition have been conducted on patients

Strategies to inhibit TNF- in MS seemed promising in preclinical applications but have widely failed in human clinical trials due to the lack of therapeutic selectivity. During an open-label phase I trial, a monoclonal TNF- antibody was infused into two human patients exhibiting rapidly progressing disease. Subsequently, in a double-blinded, placebo controlled, multicentered phase II study, 168 relapsing-remitting MS patients were administered Lenercept, a sTNF-R1 fusion protein that neutralizes TNF-. Lenercept-treated individuals experienced higher occurrence of relapse and increased neurological deficits (Van oosten et al., 1996). The ineffectiveness of anti-TNF- therapy in MS may be a consequence of divergent roles for the TNF receptors, considering that blocking TNF-R1 in mouse models dampens disease severity, while suppressing TNF-R2, the receptor that induces remyelination and harbors immunosuppressive properties, results in exacerbated disease (Arnett et al., 2001; Kassiotis et al., 2011). Recently, pharmacological agents selectively targeting TNF-R1 have been investigated. Using phage display technology, a TNF-R1 antagonist was developed and upon evaluation in mice it was found that administration of this selective antagonist improved clinical scores, reduced cerebral demyelination and suppressed the number of infiltrating inflammatory cells (Nomura et al.,

TNF- intervention in AD has been evaluated in open-labeled phase I clinical trials where perispinal extrathecal administration of Etanercept was administered weekly to a small number of patients ranging from mild to severe AD for a short duration of 6 months that claimed substantial cognitive and behavioural improvements, including verbal fluency and aphasia (Tobinick et al., 2006; Tobinick et al., 2008). Currently a phase II study is recruiting to evaluate the safety and tolerability of Etanercept in AD. These results seem promising but conclusions regarding the promise of such a therapeutic strategy should be reserved until after extensive chronic suppression of TNF- activity is performed in preclinical models and double-blind human clinical trials have been conducted and results critically reviewed by

Trails on the immunological hypothesis in ALS are not yet established although TNF system implications have been described for a long time. This therapeutic approach was not considered using neither synthetic TNF--receptor inhibitors nor monoclonal anti-TNF-

There is no doubt that TNF- play key roles in degenerative conditions afflicting CNS, also in ALS. The precise role TNF- plays remain highly controversial due to the complexity and pleiotropic nature of this cytokine and its activities during critical developmental and homeostatic cellular processes. Multiple factors determine whether TNF- will exert deleterious or beneficial effects for neuronal survival and some of these differential actions relate to its duration of expression, concentration, receptor conformation. Despite the

reactions and systemic side effects (Scheinfeld et al., 2006).

with Multiple Sclerosis (MS) and Alzheimer disease (AD).

2011).

the research community.

antibody.

**6. Conclusions** 


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**19** 

*U. S. A.* 

**Stem Cell Application for Amyotrophic** 

Masatoshi Suzuki, Chak Foon Tso and Michael G. Meyer

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

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 (Boillée 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 (Boillée et al., 2006a). Of course there are a lot of shortcomings for using

only increases survival by a matter of months (Zoccolella et al., 2009).

**1. Introduction** 

**1.1 ALS and the SOD1 rodent models** 

**Lateral Sclerosis: Growth Factor** 

**Delivery and Cell Therapy** 

*University of Wisconsin-Madison* 

