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Abstract
Background Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by simultaneous activation of the innate and adaptive arms of the immune system. The progression of the disease is unpredictable, making its treatment a challenge. Recently the nuclear export protein Exportin 1 (XPO1, also known as CRM1) has surfaced as an attractive target for the treatment of SLE and other inflammatory disorders. Selective Inhibitor of Nuclear Export (SINE) compounds are potent, orally available and well-tolerated XPO1 inhibitors. SINE compounds exert apoptotic and anti-inflammatory effects by mediating nuclear retention of important XPO1 cargos like the NFκB pathway regulatory protein, IκB.
Objectives Based on the central role of NFκB signaling in the activation of immune cells in SLE, we decided to evaluate the therapeutic ability of SINE compounds to modulate experimental lupus progression.
Methods To evaluate the efficacy of SINE compounds in a preclinical model of SLE, cohorts of lupus-prone mice with established disease (elevated anti-dsDNA antibody titer and proteinuria) were dosed with SINE compound or vehicle. We used flow cytometry to enumerate immune cells and immunofluorescence to visualize germinal centers (GC) in spleen. Quantitative PCR was used to measure changes in mRNA expression for molecules key in plasma cell attraction and survival, and histology was used to evaluate inflammation, antibody deposition and pathology in kidneys of lupus-prone mice.
Results We found that treatment with SINE compounds significantly prevented increases in proteinuria (proteinuria scores: Control: 2.12±1.12; SINE (5 mg/kg): 1.06±0.49; SINE (7.5 mg/kg): 0.85±0.55) and drastically decreased IgG deposition and kidney pathology (glomerulonephritis, tubule damage and perivascular cuffing). Prevention of kidney damage was associated with a remarkable disruption of splenic GC, a significant reduction in the number of auto-reactive antibody secreting cells (ASC), and a decrease in the accumulation of auto-reactive ASC in the inflamed kidney. Reduced numbers of plasma cells in the inflamed kidney are likely due to the drastic decrease in the expression of molecules critical for PC attraction (CCL2, CXCL9, CXCL10, CXCL11) and survival (BAFF, APRIL). The potent effect of SINE compounds on GC and auto-reactive ASC is noticeable as early as 1 week after starting therapy. However, kinetics studies showed that a more pronounced elimination of GC and auto-reactive ASC is achieved after 8 weeks. Although SINE therapy has a drastic impact on spleen architecture, recovery experiments showed that complete recovery of immune cells in spleen occurred by 4 weeks. The reversible impact of SINE compounds on SLE provides a potential window of time for immunization of lupus patients.
Conclusions SINE compounds have demonstrated efficacy in a murine model of SLE by reducing generation, survival and function of auto-reactive immune cells. It is likely that inhibition of the canonical NFκB pathway underlies KPT-350's inhibitory effect. Together, our findings suggest the potential of SINE compounds to have a significant impact on disease progression in SLE.
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Figure - Zhang KJ and Wang M. Chin J Cancer Res 24(4): 380–393:2012.
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Disclosure of Interest J. Rangel-Moreno Grant/research support from: NIH Small Business Innovation Research grant, S. Cochran Employee of: Karyopharm Therapeutics, S. Tamir Shareholder of: Karyopharm Therapeutics, Employee of: Karyopharm Therapeutics, M. Lee Shareholder of: Karyopharm Therapeutics, Employee of: Karyopharm Therapeutics, S. Shacham Shareholder of: Karyopharm Therapeutics, Employee of: Karyopharm Therapeutics, J. Anolik Grant/research support from: NIH Small Business Innovation Research grant