Contributions
Abstract: P715
Type: Poster
Abstract Category: Therapy - disease modifying - 27 Neuroprotection and Repair
Background: Multiple sclerosis (MS) is an inflammatory demyelinating disease in which immune cells attack and destroy myelin. Despite treatment with immunomodulatory drugs, MS patients slowly transition into a progressive disease state of accumulating and irreversible neurological decline. Dimethyl fumarate (DMF) is approved for relapsing forms of MS and may protect axons through upregulation of endogenous stress resistance genes. We have developed a progressive MS mouse model consisting of three cycles of cuprizone-treatment and spontaneous recovery, engendering a significant loss of axons in the corpus callosum and progressive neurological decline between 62-77 weeks.
Objective: To determine whether early use of DMF improves behavioral outcomes and preserves corpus callosum axons in a progressive MS mouse model.
Methods: Eight-week-old C57BL/6J mice were subjected to three cycles of cuprizone/rapamycin treatment followed by remyelination. DMF treatment was started either after the first, second or third insult, and continued daily for 72 weeks. Neurological function was evaluated in the NeuroCube® (NC) platform and white matter myelin was evaluated using a myelin-loss sensitive magnetization transfer ratio (MTR) following MRI scanning.
Results: Mice receiving DMF treatment following the first insult showed significant behavioral improvements compared with mice receiving vehicle when analyzed in NC at 36-weeks (P=0.002) and continued to show significant behavior improvements at 48-weeks (P=0.009). Mice starting DMF-treatment following the second insult also showed significantly improved behavior readouts compared with mice receiving vehicle at 36-weeks (P=0.02) and 48-weeks (P=0.018). Mice receiving DMF after the third insult showed smaller improvements compared with the vehicle group when analyzed at 36-weeks (P=0.05) and 48-weeks (P=0.04).
Conclusions: DMF treatment immediately following the first insult, rather than the second or third insult, demonstrated the most significant functional improvement compared with vehicle, suggesting DMF may have neuroprotective effects in this progressive MS mouse model. Longitudinal evaluation of behavioral outcomes and white matter integrity at the 60- and 72-week time points will further characterize the long-term neuroprotective effect of DMF.
Supported by: Biogen.
Disclosure:
Brian Bai: employee of and holds stock/stock options in Renovo.
J. Simon Lunn: employee of and holds stock/stock options in Renovo.
Robin L. Avila: employee of and holds stock/stock options in Biogen.
Harsha Battapady: employee of and holds stock/stock options in Renovo.
Vivek Shenoy: employee of and holds stock/stock options in Renovo.
Brian T. Wipke: employee of and holds stock/stock options in Biogen.
Jason P. Mendoza: employee of and holds stock/stock options in Biogen.
Bruce D. Trapp: employee of and holds stock/stock options in Renovo.
Abstract: P715
Type: Poster
Abstract Category: Therapy - disease modifying - 27 Neuroprotection and Repair
Background: Multiple sclerosis (MS) is an inflammatory demyelinating disease in which immune cells attack and destroy myelin. Despite treatment with immunomodulatory drugs, MS patients slowly transition into a progressive disease state of accumulating and irreversible neurological decline. Dimethyl fumarate (DMF) is approved for relapsing forms of MS and may protect axons through upregulation of endogenous stress resistance genes. We have developed a progressive MS mouse model consisting of three cycles of cuprizone-treatment and spontaneous recovery, engendering a significant loss of axons in the corpus callosum and progressive neurological decline between 62-77 weeks.
Objective: To determine whether early use of DMF improves behavioral outcomes and preserves corpus callosum axons in a progressive MS mouse model.
Methods: Eight-week-old C57BL/6J mice were subjected to three cycles of cuprizone/rapamycin treatment followed by remyelination. DMF treatment was started either after the first, second or third insult, and continued daily for 72 weeks. Neurological function was evaluated in the NeuroCube® (NC) platform and white matter myelin was evaluated using a myelin-loss sensitive magnetization transfer ratio (MTR) following MRI scanning.
Results: Mice receiving DMF treatment following the first insult showed significant behavioral improvements compared with mice receiving vehicle when analyzed in NC at 36-weeks (P=0.002) and continued to show significant behavior improvements at 48-weeks (P=0.009). Mice starting DMF-treatment following the second insult also showed significantly improved behavior readouts compared with mice receiving vehicle at 36-weeks (P=0.02) and 48-weeks (P=0.018). Mice receiving DMF after the third insult showed smaller improvements compared with the vehicle group when analyzed at 36-weeks (P=0.05) and 48-weeks (P=0.04).
Conclusions: DMF treatment immediately following the first insult, rather than the second or third insult, demonstrated the most significant functional improvement compared with vehicle, suggesting DMF may have neuroprotective effects in this progressive MS mouse model. Longitudinal evaluation of behavioral outcomes and white matter integrity at the 60- and 72-week time points will further characterize the long-term neuroprotective effect of DMF.
Supported by: Biogen.
Disclosure:
Brian Bai: employee of and holds stock/stock options in Renovo.
J. Simon Lunn: employee of and holds stock/stock options in Renovo.
Robin L. Avila: employee of and holds stock/stock options in Biogen.
Harsha Battapady: employee of and holds stock/stock options in Renovo.
Vivek Shenoy: employee of and holds stock/stock options in Renovo.
Brian T. Wipke: employee of and holds stock/stock options in Biogen.
Jason P. Mendoza: employee of and holds stock/stock options in Biogen.
Bruce D. Trapp: employee of and holds stock/stock options in Renovo.