Novel therapeutic targets and treatments for multiple sclerosis using a murine model of experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a chronic and often debilitating demyelinating disease of the central nervous system (CNS) that afflicts approximately 2.5 million individuals worldwide. Although the exact etiology of MS remains unknown, current evidence suggests that the susceptibility of developing MS is dependent on both genetic and environmental factors. Disease progression, severity, and response to currently approved therapies are highly variable among MS patients and remains a major obstacle in treating this highly unpredictable disorder. Furthermore, many of the current treatments are costly, limited in efficacy, and possess unpleasant side effects. An increasing body of literature suggests that the pathological events contributing to MS may be attributed to the failure of myelin-reactive immune cells to undergo apoptosis. The resultant accumulation and activation of immune cells within the CNS causes inflammation and demyelination, which can lead to axonal injury. The goal of this research was to identify and validate novel therapeutic targets and treatments for MS using a murine model of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Phosphodiesterase 4 (PDE4) inhibitors are anti-inflammatory compounds that have been suggested as a possible treatment for MS. Unfortunately, many PDE4 inhibitors cause severe nausea, which has hampered their clinical development. A novel PDE4 inhibitor that does not accumulate in the CNS has recently been identified and does not produce emesis. Oral administration of this compound significantly decreased EAE severity at doses sufficient to inhibit release of several pro-inflammatory cytokines. In a series of separate experiments, X-linked inhibitor of apoptosis (XIAP), a potent anti-apoptotic protein, was elevated in peripheral and encephalitogenic T cells. Furthermore, transgenic mice engineered to overexpress XIAP (ubXIAP mice) developed a more severe EAE phenotype, accompanied by an earlier onset compared to WT-littermates. Using an antisense oligonucleotide against XIAP, EAE severity and XIAP levels in peripheral blood leukocytes were reduced. Concurrent administration of this compound and IFNbeta at sub-optimal (threshold) doses reduced the severity of EAE. Taken together, these results suggest that enhancing the apoptotic sensitivity of autoreactive immune cells may represent a novel therapeutic approach for treating MS.