Therapeutic area
MTA
Methyltioadenosine for the treatment of Multiple Sclerosis and Transplant rejection
Pablo Villoslada, MD1 and Matias Avila, PhD2
1Neuroscience and 2Hepathology and Gene Therapy Divisions. Center for Applied Medical Research. University of Navarra. Pamplona, Spain.
Methyltioadenosine
Methylthioadenosine (MTA) is a lipophilic sulfur-containing adenine nucleoside (Fig.1) produced from S-adenosylmethio-nine (SAM), during the synthesis of the polyamines spermine and spermidine 1 2. Besides its strong inhibitory effect on the polyamine biosynthesis, MTA has been shown to exert other potent and specific pharmacological effects on cellular function Experiments carried out in in vivo models have demonstrated that MTA administration can control hepatocellular proliferation, inhibit the development of neoplastic liver lesions and protect from toxic liver injury, modulate the inflammatory response 3. Indeed, we have recently reported that MTA prevented bacterial lipopolysaccharide (LPS)-induced lethality in mice, likely through the suppression of tumour necrosis factor-a (TNF-a? production and inducible nitric oxide synthase (iNOS) gene expression, and by enhancing the expression of interleukin-10 (IL-10)4.
Figure 1. Structure of Methyltioadenosine
MTA is a well-tolerated drug, devoid of the unwanted effects of other methyltranferase inhibitors. It has been previously administered in both acute and chronic experimental models of liver injury and systemic inflammation, showing efficacy and a safe profile, with an ID50 of 2.9±0.4 g/kg (i.m.) in rats. In humans, MTA is also well tolerated. Twenty-eight individuals (21-48 years old) were treated with 100 mg every 8 hours for 3 days or 600 mg per day for one month without signs of toxicity.
Multiple Sclerosis
Multiple Sclerosis (MS) is an autoimmune disease affecting two million people around the world, mainly in the well developed countries, and is the second cause of disability in young adults after traffic injury 5. MS represents a significant health and social burden because it affects young adults, many of which are going to suffer a significant disability, and because the cost of years with the disease is high 6. Pathological studies in MS brains and studies in Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS, suggest that most of the axonal and myelin damage are secondary to the inflammatory process, although some other pathogenic events might contribute to CNS damage such as excitoxicity. Because MS is diagnosed when only minor CNS damage has already occurred, as opposed to other neurodegenerative diseases such as Alzheimer disease, this suggests that if we stop the inflammatory process at the early phase of the disease we can prevent most of the brain damage and future disability. Indeed, although in the last years it has been stressed that the progressive phase of MS can be considered a neurodegenerative process, even during this chronic phase the major cause of axonal damage appears to be related to the immunopathology secondary to the autoimmune process. Thus, controlling the autoimmune response into the brain might be highly efficacious in preventing brain tissue damage, increase of disability, and may reduce the risk of progression towards the neurodegenerative phase. Currently approved therapies for MS are immunomodulatory drugs such as interferon-beta and glatiramer acetate that are only partly effective, are administered parentally and are often limited by side effects. The discovery of a new immunomodulatory agent that improves the control of the disease which might be suitable and safe for polytherapy and for oral administration will be of great medical interest.
Immunomodulatory properties of Methyltioadenosine in the animal model of Multiple Sclerosis
Studies conducted in our center demostrated that MTA is able to prevent the acute animal model of multiple sclerosis (EAE, Fig. 2A) as well as ameliorate the disease course of the chronic animal model (chronic-relapsing EAE, Fig.2B) that better mimicks the course of the disease 7.
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| Figure 2A. Prevention of acute EAE by MTA | Figure 2B. Amelioration of chronic-relapsing EAE by MTA |
Mechanism of action of MTA for the treatment of autoimmune diseases
MTA treatment markedly inhibited brain inflammation and reduced brain damage. Administration of MTA suppressed T cell activation in vivo and in vitro, likely through a blockade in T cell signalling resulting in the prevention of inhibitor of kappa B (IkB-a? degradation and in the impaired activation transcription factor NF-kB. Indeed, MTA suppressed the production of pro-inflammatory genes and cytokines (interferon-g, tumour necrosis factor-a and inducible nitric oxide synthase) and increased the production of anti-inflammatory cytokines (interleukin-10). The mechanism through which MTA seems to operate is by modulating the methylation process in proteins and DNA. In addition MTA have anti-oxidant properties and can modulate Adenosine receptor pathway. MTA has a remarkable immunomodulatory activity and may be beneficial for MS and other autoimmune diseases.
References:
Pegg AE. Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy. Cancer Res. 1988;48:759-774
Williams-Ashman HG, Seidenfeld J, Galletti P. Trends in the biochemical pharmacology of 5'-deoxy-5'-methylthio- adenosine. Biochem.Pharmacol. 1982;31:277-288
Pascale RM, Simile MM, De Miglio MR, Feo F. Chemoprevention of hepatocarcinogenesis: S-adenosyl-L-methionine. Alcohol. 2002;27:193-198
Hevia H, Varela-Rey M, Corrales FJ et al. 5'-methylthio-adenosine modulates the inflammatory response to endotoxin in mice and in rat hepatocytes. Hepatology. 2004;39:1088-1098
Hauser SL, Oksenberg JR. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron. 2006;52:61-76
Olesen J, Leonardi M. The burden of brain diseases in Europe. Eur.J.Neurol. 2003;10:471-477
Moreno B, Hevia H, Santamaria M et al. Methylthioadenosine reverses brain autoimmune disease. Ann.Neurol. 2006;60:323-334
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