Development of a novel accurate therapy for Multiple Sclerosis

PROJECT SUMMARY Multiple SclerosisMSis the most common neurological disease of early adulthood and is mediated by autoimmune mechanisms that lead to demyelination and neuronal damage in the central nervous systemresulting in progressive neurological dysfunctionUp to datethere is no cure for the disease and current available treatments focus on preventing future immunological attacksprimarily by suppressing the immune systemand this has adverse side effects that are often severe or fatalAccordinglythere is a clear unmet need for the development of effective and well tolerated therapies to arrest MS developmentThis has been challenging because MS has multiple etiologiesandgtgenes identified as risk factors for MS so farand the molecular mechanisms underlying these etiologies are not well understoodWe uncovered the molecular underpinnings of an MS etiology and hope that this knowledge will translate into an accurate therapy for MSThe etiology in question is associated with the interleukinreceptorIL Rgenewhich encodes a cell surface receptor in T cellshereafter referred to as mIL Rthat plays a central role in the homeostasis of T cellsWe previously identified the genetic variant rswithin exonof IL R to be strongly associated with increased MS riskFurthermorewe showed that the risk allele of this variant increases exclusionskippingof the alternative exonleading to a higher fraction of mRNAs encoding a secreted form of the receptorsIL Rleading to elevated levels of circulating sIL RThis has important repercussions in the development of MS because sIL R has been shown to aggravate the progression and severity of the disease in the Experimental Autoimmune EncephalomyelitisEAEmouse model of MSHerewe propose to develop a novel biologic MS drug centered on preventing formation of the pathogenic sIL RGiven that sIL R is produced by exclusion of exonfrom IL R mRNAsour strategy is to generate splicing modulating antisense oligonucleotidesASOsto correct splicing of IL R exonand restore expression of IL R protein isoformsOur approach represents a major improvement over current MS therapies in that by correcting IL R splicingit will diminish expression of the pathogenic sIL R isoformwithout reducing expression of the mIL RThis is important because mIL R function is essential for proper immune function and its disruption leads to immunodeficiencyThereforeour biologic drugunlike current MS drugswill not cause immunosuppressionFurther supporting a role of IL R in the development of autoimmunitythis gene has been associated with other autoimmune diseases including Type I DiabetesT DRheumatoid ArthritisRAand Systemic Lupus ErythematosusSLEand most importantlypatients of these diseases have been shown to have elevated levels of circulating sIL RAccordinglythe approach proposed here has the potential to yield the first accurate therapy for MS and several autoimmune diseases associated with elevated levels of sIL R PROJECT NARRATIVE Multiple SclerosisMSis a demyelinating autoimmune disorder of the central nervous system that causes progressive neurological dysfunction and disability in young adultsand this represents a major socioeconomical burden for the patients and societyThere is no curative treatment for this devastating disease and the current drugswhile providing hopeare far from ideal as they are immune modulators that cause adverse side effects associated with broad immunosuppressionThe research proposed here aims to develop an effective and safer accurate MS therapy that avoids immunosuppressionwhich is a critical unmet need in MS