Therapeutic area

MTA

Methyltioadenosine for the treatment of Multiple Sclerosis and Transplant rejection

Due to the potential safety, oral availability, potency and synergy with other immunomodulatory drugs, MTA could be developed as a single as well as a combination therapy for Multiple Sclerosis with higher efficacy and lower or no side-effects than current disease modifying drugs.

In addition, MTA exerts a neuroprotective activity that protects against loss of neurons and may be a more complete therapy for Multiple Sclerosis in the long term.

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system. It is the most common chronic neurologic disease in young people and adults in Europe and affects approximately 2.5 million people throughout the world. Some current therapies such as Interferon beta or Glatiramer Acetate are able to modify disease course but their efficacy is limited, it requires frequent injections and they have common side effects. For this reason, a more effective oral therapy well tolerated for the long term is needed.

Methylthioadenosine (MTA) is a naturally occurring lipophilic sulfur-containing adenine nucleoside present in all mammalian tissues produced from S-adenosylmethionine during the synthesis of the polyamines spermine and spermidine. Using the animal model of MS, the experimental autoimmune encephalomyelitis (EAE), it was found that oral administration of MTA is able to prevent acute EAE and, more importantly, to ameliorate chronic-relapsing EAE which resembles the clinical situation found in humans more closely. This pharmacological effect is achieved by an immunomodulatory activity that was also observed in peripheral blood mononuclear cells from patients with MS.

MTA exerts its activity in a dose–response manner, the highest dose tested being more effective than first line therapies for MS such as Interferon beta or Glatiramer Acetate at the common doses. Besides, MTA showed an interesting profile in combination therapy mostly with Glatiramer Acetate, with higher efficacy than individual therapies and with no obvious signs of related toxicity such as weight loss or changes in hepatic enzymes. This is in agreement with previous reported phase I studies of oral MTA administration in volunteers treated up to 1 month who did not report any side effects.

Current disease-modifying therapies in MS consist primarily of anti-inflammatory drugs but MS progression leads to substantial irreversible damage and loss of neurons, resulting in brain atrophy and cumulative disability. MTA has shown a neuroprotective activity protecting astrocytes and neurons from the cerebral cortex from the deprivation of oxygen and glucose, hippocampal neurons from cell death after global ischemia, oligodendrocytes from excitotoxicity and optic nerve tissue damage after ischemia, and mixed glial-neuronal cultures from excitotoxicity. Taken together, these results indicate that MTA not only exerts an immunomodulatory activity, but also a neuroprotective activity.