**Author details**

Jin Hee Shin1\* and Jae Keun Lee2

\*Address all correspondence to: ppzini@hanmail.net

1 GNT Pharma, South Korea

2 School of Life Science and Biotechnology, Korea University, South Korea

### **References**

therapeutic strategies and drugs developed based on them, as shown in Figure 1, explain the multiple-disease-causing process of ALS. As shown in Table 1, many drugs were evaluated in mice that expressed mutant SOD1. Most of the drugs were beneficial to the motor function and survival in the tests with the mice. Several drugs (such as creatine, celecoxib, gabapentin, topiramate, lamotrigine, minocycline, thalidomide, valproate, vitamin E, and even lithium) showed beneficial effects in animal ALS models, but none of them significantly prolonged the survival or improved the quality of life of human ALS patients. The therapeutic effects on the animal models and the human patients significantly differed due to the following translational mismatch issues: first, the methological inappropriateness of the drug screening with the use of animals that had biological confounding variables such as sex and differences in the treatment initiation time point; second, the lack of correct pharmacokinetics, which were considered in a dose-ranging study of safety/toxicity and BBB penetration; and finally, the methodological pitfall of ALS clinical trials due to the insufficiency of the number of patients, the inclusion of heterogeneous populations, the short duration of the trial, and the inadequate analysis of the efficacy. It should be noted that the combination of creatine and celecoxib improved the motor function in a randomized clinical phase II trial of ALS patients and SOD1G93A mice, although single treatment with either creatine or celecoxib failed to show beneficial effects in human ALS trials [208], which suggests the greater efficacy of combined anti-oxidant and NSAID therapy than those of monotherapy. Several pieces of evidence support the notion that therapeutic combinations are more effective than individual agents in animal ALS models (Table2). More recently, the authors reported that a single agent named

**Compound Dose Survival Reference**

**Creatine 2% 12% Zhang W et al., 2003 [117]**

**Creatine 2% 20% Klivenyi P et al., 2004 [169]**

**Rasagiline 2 mg/kg 14% Waibel et al., 2004 [224]**

**Neu2000 30 mg/kg 15% Shin et al., 2007 [96]**

**Lithium 60 mg/kg 8% Feng H et al., 2008 [212]**

 **Minocycline/ Riluzole/ Nimodipine 80 + 40 +30 (mg/kg) 13% Kriz et al., 2003 [223]**

**Riluzole 7.5% Del Signore Sj et al., 2009 [222]**

**Minocycline 22mg/kg 13% Creatine/Minocycline 25%**

50 Current Advances in Amyotrophic Lateral Sclerosis

**Celecoxib 0.012% 21% Rofecoxib 0.005% 19% Creatine/Celecoxib 29% Creatine/Rofecoxib 31%**

**Riluzol 30 mg/kg 11% Rasagiline/Riluzol 20%**

**Lithium 2% 10% Neu2000/Lithium 2% 22%**

**Valproic acid 300 mg/kg 10% Lithium/ VPA 15%**

**Sodium phenylbutyrate 12.8% Riluzole/Sodium phenylbutyrate 21.5%**

**Table 2.** Additive effect of combination therapy in ALS mice


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**Chapter 3**

**Genetics of ALS and Correlations Between Genotype and**

Amyotrophic Lateral Sclerosis, generally known as ALS, is a lethal neurodegenerative disease that gradually affects the motor neurons (nerve cells) which control muscle movement. The causes of the disease are as yet unknown and the substantial amount of research currently under way has found that the causes of ALS are multifactorial, such as genetic predisposition. In fact, about the involvement of genetic, ALS is a multigenic disease result from mutations in more than one gene (Table 1). The annual incidence of ALS is 0,4-1,76 per 100000 [1]. The majority of cases of ALS are sporadic (90-95%), called SALS. Around 5-10% of cases are considered to be familial (FALS), where the disease is present in both a proband and firstdegree or second-degree relative [2-3]. FALS is usually inherited in an autosomal dominant manner, though there are rare cases of autosomal recessive disease. FALS is genetically heterogeneous, including 15 mapped loci, of which the causative genes are identified for 11. Mutations in several of the known FALS genes have also been described in apparently sporadic cases of ALS at low frequencies. Genetic changes detected in sporadic cases arise both from new mutations and also lack of evidence of inheritance due to the difficulty in recognizing a genetic component to rapidly lethal late-onset disease. The systematic, detailed diagnosis of neurological disease in older people is a modern, and still incomplete, medical phenomenon. For any late-onset disorder both incomplete penetrance and premature death of earlier generations due to other causes attenuates the expression of disease within a family so that in many examples where apparently sporadic ALS is associated with genetic mutation there is limited information about the family rather than a clear demonstration of unequivocally de

> © 2013 Diamanti et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Phenotype in ALS — A Focus on Italian Population**

L. Diamanti, S. Gagliardi, C. Cereda and M. Ceroni

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/56547

**1. Introduction**

novo genetic change [4].
