Contributions
Abstract: P668
Type: Poster
Abstract Category: Therapy - disease modifying - Neuroprotection
Background: The nuclear export protein XPO1 (CRM1) has surfaced as an attractive target for the treatment of neurologic and inflammatory disorders like multiple sclerosis (MS), as well as various viral infections. Selective Inhibitor of Nuclear Export (SINE) compounds are potent, orally-bioavailable, and well-tolerated XPO1 inhibitors. Here, we evaluate the neuroprotective and anti-inflammatory effects of SINE compounds in a preclinical model of MS and highlight their therapeutic potential for the treatment of MS and related viral infections.
Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in female, C57BL/6J mice on day 0. At the onset of hind-limb paralysis (~ day 16), mice were dosed via oral gavage with either vehicle or SINE compound (75 mg/kg KPT-276 or 7.5 mg/kg KPT-350 QoD for 12 days). Clinical symptoms and hind-limb locomotor function were monitored. Mice were sacrificed on day 28 and spinal cords were removed, sectioned and treated with H&E for histopathological characterization or PBS for flow cytometry (FACS) analysis. Finally, an in vitro screen of SINE compound activity against a panel of 51 viruses was conducted.
Results: SINE compounds slowed the progression of EAE symptoms with no overt signs of toxicity. Vehicle-treated mice progressed to full quadriplegia, while the motor activity of SINE-treated mice improved substantially (% change in disease score vs. vehicle: KPT-276: - 60%, KPT-350: -75%). Histopathological characterization demonstrated preserved axonal integrity in demyelinated axons and reduced inflammatory lesions in the lumbosacral spinal cord. FACS analysis of immune cells in the spinal cord after SINE compound treatment showed a reduction in CD45+ leukocytes, B220+ B cells, and CD4+ and CD8+ T cells vs. vehicle. Furthermore, SINE compounds inhibited the replication of >25 viruses, including 5 suspected causes of MS pathogenesis, relapse and comorbidity: JC virus, EBV, HSV, influenza A H1N1, and adenovirus.
Conclusion: SINE compounds halt the symptoms of demyelination in a murine model of MS by modulating aberrant subcellular transport in neurons and immune cells, thereby reducing the inflammatory infiltrates and enhancing neuroprotection. These compounds also reduce viral replication with broad-spectrum effect. Collectively, these findings suggest the unique potential of SINE compounds to act as combined immunomodulatory, neuroprotective and antiviral treatments for MS and related viral infections.
Disclosure:
Tamir: employee of Karyopharm Therapeutics, Inc.;
Haines: nothing to disclose;
Herbin: nothing to disclose;
Alexandropoulos: nothing to disclose;
Landesman: employee of Karyopharm Therapeutics, Inc.;
McCauley: employee of Karyopharm Therapeutics, Inc;
Shacham: executive of Karyopharm Therapeutics, Inc.;
Casaccia: nothing to disclose.
Abstract: P668
Type: Poster
Abstract Category: Therapy - disease modifying - Neuroprotection
Background: The nuclear export protein XPO1 (CRM1) has surfaced as an attractive target for the treatment of neurologic and inflammatory disorders like multiple sclerosis (MS), as well as various viral infections. Selective Inhibitor of Nuclear Export (SINE) compounds are potent, orally-bioavailable, and well-tolerated XPO1 inhibitors. Here, we evaluate the neuroprotective and anti-inflammatory effects of SINE compounds in a preclinical model of MS and highlight their therapeutic potential for the treatment of MS and related viral infections.
Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in female, C57BL/6J mice on day 0. At the onset of hind-limb paralysis (~ day 16), mice were dosed via oral gavage with either vehicle or SINE compound (75 mg/kg KPT-276 or 7.5 mg/kg KPT-350 QoD for 12 days). Clinical symptoms and hind-limb locomotor function were monitored. Mice were sacrificed on day 28 and spinal cords were removed, sectioned and treated with H&E for histopathological characterization or PBS for flow cytometry (FACS) analysis. Finally, an in vitro screen of SINE compound activity against a panel of 51 viruses was conducted.
Results: SINE compounds slowed the progression of EAE symptoms with no overt signs of toxicity. Vehicle-treated mice progressed to full quadriplegia, while the motor activity of SINE-treated mice improved substantially (% change in disease score vs. vehicle: KPT-276: - 60%, KPT-350: -75%). Histopathological characterization demonstrated preserved axonal integrity in demyelinated axons and reduced inflammatory lesions in the lumbosacral spinal cord. FACS analysis of immune cells in the spinal cord after SINE compound treatment showed a reduction in CD45+ leukocytes, B220+ B cells, and CD4+ and CD8+ T cells vs. vehicle. Furthermore, SINE compounds inhibited the replication of >25 viruses, including 5 suspected causes of MS pathogenesis, relapse and comorbidity: JC virus, EBV, HSV, influenza A H1N1, and adenovirus.
Conclusion: SINE compounds halt the symptoms of demyelination in a murine model of MS by modulating aberrant subcellular transport in neurons and immune cells, thereby reducing the inflammatory infiltrates and enhancing neuroprotection. These compounds also reduce viral replication with broad-spectrum effect. Collectively, these findings suggest the unique potential of SINE compounds to act as combined immunomodulatory, neuroprotective and antiviral treatments for MS and related viral infections.
Disclosure:
Tamir: employee of Karyopharm Therapeutics, Inc.;
Haines: nothing to disclose;
Herbin: nothing to disclose;
Alexandropoulos: nothing to disclose;
Landesman: employee of Karyopharm Therapeutics, Inc.;
McCauley: employee of Karyopharm Therapeutics, Inc;
Shacham: executive of Karyopharm Therapeutics, Inc.;
Casaccia: nothing to disclose.