Evaluating the impact of novel inhibitors of nuclear pore export in SLE

Systemic lupus erythematosusSLEis a complex autoimmune disease with a broad spectrum of clinical manifestations that affect several organsSLE affects millions of individualswith women and minorities disproportionately burdenedand is associated with significant morbidity and mortalityDespite considerable progress made towards understanding the disease and the identification of the central roles plasma cellsPCsand autoreactive antibody secreting cellsASCsplay in SLE pathogenesismost therapeutic approaches remain broadly immunosuppressiveanti inflammatoryor palliativewhich highlights the urgent need for novel therapiesDue to the essential role of auto antibodies in the amplification of auto immunitya goal in lupus therapy is the elimination of auto reactive ASCsKaryopharm Therapeutics pioneered the development of Selective Inhibitors of Nuclear ExportSINEand is investigating their utility in auto immune diseases in collaboration with the Anolik laboratory at the University of Rochester Medical CenterTogether we have shown that inhibiting nuclear export with KPTa SINEstrongly and selectively ablates auto reactive PCs by targeting pathways that are critical for their generationsurvivaland recruitment into inflamed kidneysSpecificallywe have shown that KPTselectively inhibits the production of auto reactive ASCs and has a compelling effect on B cell germinal center formation stabilityprevents expansion of memory T follicular helper cellsand markedly reduces mRNA expression of molecules critical for survival and recruitment of auto reactive ASCsIn the proposed projectwe will further define the efficacy of SINE treatment and identify viable combination and maintenance therapies to accelerate the translation of these novel compounds into SLE clinical trialsIn Aimwe will define the optimal dosage conditions to restrain murine lupus progression after withdrawal of SINE therapy byidetermining the duration of the SINE effect and defining the need for maintenance therapyandiidefining the duration of the SINE effect on NF B inhibitionIn Aimwe will examine the effects of combination modality therapy on murine autoreactive PCs byievaluating the efficacy and duration of SINE and proteasome inhibitors on autoimmune disease relapseiidetermining the effects of single vs combination therapy on PCs in SLEandiiidefining the impact of factors involved in the maintenance of autoreactive PCsFinallyAimwill expand our studies to human SLE byidefining the role of NF B survival signals in SLE patient PCsiiexamining the effect SINE treatment has on SLE PC survivaliiidefining the signals required for SLE bone marrowBMPC survivalividentifying the source of PC survival factors in the BMandvdemonstrating that SINE therapy inhibits B cell differentiationOur goal is to delineate an efficacious combination dosing strategyusing a novel approach that targets key synergistic pathways in SLE disease pathogenesiswith the long term goal of delivering an improved therapy for SLESuccessful completion of these studies will allow us to pursue commercialization objectives and move SINE compounds into extensive preclinical safety testing Systemic Systemic lupus erythematosusSLEis a complex autoimmune disease affecting multiple organs and with limited treatment optionsWe seek to investigate the potential utility of Selective Inhibitors of Nuclear ExportSINEcompounds in auto immune diseases like SLE