Sphingosine-1-phosphate system as a therapeutic target for amyotrophic lateral sclerosis

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Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, and untreatable neurological disease characterized by muscle weakness, atrophy and spasticity, typically leading to paralysis and death within 3-5 years after symptom onset. Pathologically, ALS is primarily characterized by the degeneration and death of motor neurons (MN) in the cerebral cortex and spinal cord. Damage to MN is associated with the onset of ALS however the progressive loss of motor neurons is a non-cell autonomous process that requires damage of neighboring non- neuronal cells. Indeed, the presence of reactive astrocytes and microglia in heavily-affected areas is a hallmark of ALS. Deregulation of lipid metabolism and malfunction of the immune system have been implicated in the pathogenesis of ALS. Sphingolipid metabolism was identified as the most dysregulated pathway, and ceramide species, which promote apoptosis and inflammation, were found to accumulate in postmortem spinal cord samples of ALS patients. Influx of T lymphocytes into the central nervous system occur early in the disease. While some lymphocytes activate neuroinflammation others, regulatory T cells (Tregs), hold neuroinflammation in check. Protective and harmful phenotypes of microglia and astrocytes appear to coexist in affected tissue. The fact that immunosuppressant treatments have been disappointing in ALS may be because of the dual nature of the immune system. Fingolimod is a structural analog of sphingosine that has been approved for the oral treatment of multiple sclerosis. Unlike conventional immunosuppressive drugs, fingolimod does not inhibit lymphocyte activation but reduces the migration of pathogenic lymphocytes into the central nervous system (CNS) and increases the number of circulating Tregs. Fingolimod readily crosses the blood brain barrier and in the CNS, promotes the neuroprotective phenotype in glial cells. In a recent preclinical study, fingolimod improved the survival rate of SOD1-G93A mice, a mouse model of ALS, and the beneficial effect was associated with modulation of microglial activation and innate immunity. We propose a study to test the hypothesize that altered the S1P signaling drives the proinflammatory activation of astrocytes and microglia in ALS and that treatment with S1P modulators will interfere with the proinflammatory process to slow down (or recover) the degeneration of MN with the ultimate goal of paving the way to find new therapies to treat or cure the disease. In Aim 1 we will use two different mouse models of ALS (SOD1-G93A and TDP43-Q331K) and human postmortem lumbar cord samples from ALS patients to investigate the S1P system in the etiology ALS to establish the rational for using modulators of the S1P signaling system for the treatment of ALS. In Aim 2 we will perform a dose-response study (1, 0.3, 0.1, and 0.03 mg/kg/day) starting at a pre- or post-onset stage using fingolimod that acts on S1P1,3,4,5 and AUY954, a second generation S1P modulators with specificity to S1P1. In Aim 3 we will determine anatomical differences in the spinal cord of treated and untreated ALS mice using ex-vivo magnetic resonance (MR) imaging, a technique with high potential to translate to humans. The study incorporates principles of rational pharmacology and clinical evaluation combined with state-of-the-art neuropathological, neurochemical, and MR spectroscopy and imaging techniques to define the therapeutic benefits of S1P modulators and will provide valuable data towards understanding the pathological process of ALS and finding new approaches to treat, diagnose, and monitor the disease.