Contributions
Abstract: P402
Type: Poster Sessions
Abstract Category: Clinical aspects of MS - Neuro-ophthalmology
Background: Therapies with potential to remyelinate the central nervous system constitute one of the most promising therapeutic developments in the pipeline to treat multiple sclerosis. We completed the first positive double-blind placebo-controlled human trial for a remyelinating therapy in MS using visual evoked potentials(VEP) as an outcome. We unequivocally demonstrated improvement in longstanding latency delay on VEP for patients during the period on treatment despite the chronicity of injury. A full understanding of visual system injury in animals could enhance the ready and robust adaptation of these techniques for additional human clinical trials - and the appropriate interpretation of trial results.
Methods: We obtained VEP from C57BL/6J mice using an Espion Diagnosys system (Diagnosys LLC, Littleton,MA). We induced EAE with myelin oligodendrocyte glycoprotein 35-55 in female 8-week-old mice using adjuvant-injected mice as controls. Toxic demyelination was induced with 5 weeks of cuprizone diet. IHC for CASPR was performed on optic nerve sections. Electron microscopy of mice optic nerves was performed using a JEOL1200EXII transmission electron microscope.
Results: We found that prolongation of VEP latency precedes clinical onset of disease in EAE. VEP latency is delayed from the 5th day after immunization. N1 delay increase till day 18, with a consequent conduction improvement. Quantification of optic nerve IHC for CASPR in EAE mice mirrors the VEP delay, showing the histopathologic substrate of N1 delay. Clemastine is effective in improving VEP in EAE 7days post immunization(p=0.0002), maintaining its effect at day 21(p=0.018)and day 28(p=0.03). Cuprizone diet also provokes N1 latency delay(p=0.003). Clemastine is effective in enhancing remyelination, more quickly than expected after suspending the toxic demyelinating diet(p=0.03). Optic nerve EM showed reduced unmyelinated axons and increased remyelinating axons in mice treated with Clemastine. CASPR staining of optic nerves shows a higher number of paranodes in treated mice.
Conclusions: Here, we show that VEP latency correlates with quantitative measures of myelin from histopathology in mouse models of both inflammatory and chemical visual pathway demyelination. Furthermore, VEP latency delay improves after treatment with a tool remyelinating compound in both models, mirroring quantitative/qualitative myelin assessment and providing support for use of this approach for screening other molecules
Disclosure: Christian Cordano was supported by a training/research fellowship FISM (Fondazione Italiana Sclerosi Multipla. cod 2013/B/4)
Garrett Timmons: Nothing to disclose
Karin Stebbins: Previously employee of Inception Science. Currently employee of Pipeline therapeutics
Hao Yiu: Nothing to disclose
Michael Devereux: Nothing to disclose
Caroline Guglielmetti: Nothing to disclose
Jung Hyung Sin: Nothing to disclose
Lucas Schirmer: Research support from the National Multiple Sclerosis Society (Postdoctoral Fellowship),
Andres Cruz-Herranz: Research support from the National Multiple Sclerosis Society (Postdoctoral Fellowship), UCSF Program for Breakthrough Biomedical Research (Postdoctoral Independent Research Award), and the Conrad N. Hilton Foundation (Pilot Innovator Award).
David Rowitch: Nothing to disclose
Brian Stearns: Previously employee of Inception Science. Currently employee of Pipeline therapeutics
Daniel Lorrain: Previously employee of Inception Science. Currently employee of Pipeline therapeutics.
Jonah R Chan; Research support from NIH and NINDS
Ari J Green: Research support from the National Multiple Sclerosis Society (Harry Weaver Neurosciences Scholar Award), Novartis, UCSF CTSI, That Man May See, and the Conrad N. Hilton Foundation (Pilot Innovator Award); personal fees from Inception Sciences and Mylan Pharmaceuticals; philanthropic support from the Rachleff Family and the Robert Dale Family. He also reports serving on an end point adjudication committee for Biogen and Medimmune. He serves on trial steering committees for Novartis and Scientific Advisory Board for Bionure.
Abstract: P402
Type: Poster Sessions
Abstract Category: Clinical aspects of MS - Neuro-ophthalmology
Background: Therapies with potential to remyelinate the central nervous system constitute one of the most promising therapeutic developments in the pipeline to treat multiple sclerosis. We completed the first positive double-blind placebo-controlled human trial for a remyelinating therapy in MS using visual evoked potentials(VEP) as an outcome. We unequivocally demonstrated improvement in longstanding latency delay on VEP for patients during the period on treatment despite the chronicity of injury. A full understanding of visual system injury in animals could enhance the ready and robust adaptation of these techniques for additional human clinical trials - and the appropriate interpretation of trial results.
Methods: We obtained VEP from C57BL/6J mice using an Espion Diagnosys system (Diagnosys LLC, Littleton,MA). We induced EAE with myelin oligodendrocyte glycoprotein 35-55 in female 8-week-old mice using adjuvant-injected mice as controls. Toxic demyelination was induced with 5 weeks of cuprizone diet. IHC for CASPR was performed on optic nerve sections. Electron microscopy of mice optic nerves was performed using a JEOL1200EXII transmission electron microscope.
Results: We found that prolongation of VEP latency precedes clinical onset of disease in EAE. VEP latency is delayed from the 5th day after immunization. N1 delay increase till day 18, with a consequent conduction improvement. Quantification of optic nerve IHC for CASPR in EAE mice mirrors the VEP delay, showing the histopathologic substrate of N1 delay. Clemastine is effective in improving VEP in EAE 7days post immunization(p=0.0002), maintaining its effect at day 21(p=0.018)and day 28(p=0.03). Cuprizone diet also provokes N1 latency delay(p=0.003). Clemastine is effective in enhancing remyelination, more quickly than expected after suspending the toxic demyelinating diet(p=0.03). Optic nerve EM showed reduced unmyelinated axons and increased remyelinating axons in mice treated with Clemastine. CASPR staining of optic nerves shows a higher number of paranodes in treated mice.
Conclusions: Here, we show that VEP latency correlates with quantitative measures of myelin from histopathology in mouse models of both inflammatory and chemical visual pathway demyelination. Furthermore, VEP latency delay improves after treatment with a tool remyelinating compound in both models, mirroring quantitative/qualitative myelin assessment and providing support for use of this approach for screening other molecules
Disclosure: Christian Cordano was supported by a training/research fellowship FISM (Fondazione Italiana Sclerosi Multipla. cod 2013/B/4)
Garrett Timmons: Nothing to disclose
Karin Stebbins: Previously employee of Inception Science. Currently employee of Pipeline therapeutics
Hao Yiu: Nothing to disclose
Michael Devereux: Nothing to disclose
Caroline Guglielmetti: Nothing to disclose
Jung Hyung Sin: Nothing to disclose
Lucas Schirmer: Research support from the National Multiple Sclerosis Society (Postdoctoral Fellowship),
Andres Cruz-Herranz: Research support from the National Multiple Sclerosis Society (Postdoctoral Fellowship), UCSF Program for Breakthrough Biomedical Research (Postdoctoral Independent Research Award), and the Conrad N. Hilton Foundation (Pilot Innovator Award).
David Rowitch: Nothing to disclose
Brian Stearns: Previously employee of Inception Science. Currently employee of Pipeline therapeutics
Daniel Lorrain: Previously employee of Inception Science. Currently employee of Pipeline therapeutics.
Jonah R Chan; Research support from NIH and NINDS
Ari J Green: Research support from the National Multiple Sclerosis Society (Harry Weaver Neurosciences Scholar Award), Novartis, UCSF CTSI, That Man May See, and the Conrad N. Hilton Foundation (Pilot Innovator Award); personal fees from Inception Sciences and Mylan Pharmaceuticals; philanthropic support from the Rachleff Family and the Robert Dale Family. He also reports serving on an end point adjudication committee for Biogen and Medimmune. He serves on trial steering committees for Novartis and Scientific Advisory Board for Bionure.