Financial Disclosure. Overview. Optic Nerve. Optic Neuritis. Optic Neuritis: Course

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1 Optic Neuritis as a Model Disease to Examine Novel Neuroprotective Strategies Kenneth S. Shindler, MD, PhD Associate Professor of Ophthalmology and Neurology University of Pennsylvania Scheie Eye Institute F.M. Kirby Center for Molecular Ophthalmology Financial Disclosure The presenter has/is receiving current or past research funding from the National Institutes of Health/National Eye Institute, National Multiple Sclerosis Society, Research to Prevent Blindness, and the F. M. Kirby Foundation, as well as internal funds from the University of Pennsylvania. MP21 was provided by Mitochon Pharmaceuticals, Inc. ST266 was provided by Noveome Biotherapeutics, Inc. The presenter has a consulting agreement and has received unrestricted research funding from Noveome Biotherapeutics, Inc. Overview Describe clinical features and time course of optic neuritis supporting neuroprotective studies Discuss neuronal loss, including oxidative stress, mitochondrial dysfunction and axon degeneration, in animal models of optic neuritis Optic Nerve Comprised of retinal ganglion cell axons Optic nerve is comprised of axons of retinal ganglion cells (RGCs) Optic nerve forms cable connecting to the brain Highlight ability of novel therapeutic strategies to reduce oxidative stress, prevent neuronal loss, and preserve neurological function GCL = ganglion cell layer RGC axons converge at optic nerve head NEI Catalog number NEA9 Optic Neuritis Inflammatory demyelinating disease of the optic nerve Isolated optic neuritis or Associated with brain and spinal cord inflammation = multiple sclerosis (MS) About 5% of patients either have MS or develop MS within 1 years Optic Neuritis: Course Progressive vision loss x 1-2 wk Vision varies from 2/2 no light perception 95% recover to 2/4 or better over several weeks 4-6% have some permanent vision loss (visual acuity, contrast sensitivity, color vision, or visual field) 1

2 Optic Neuritis: Neuronal Loss Significant retinal ganglion cell (RGC) axonal loss occurs following optic neuritis Retinal nerve fiber layer (NFL) thinning on OCT or scanning laser polarimetry (Steel and Waldock, J. Neurol. Neurosurg. Psychiatry 1998, 64:55-9; Parisi et al, Invest. Ophthalmol. Vis. Sci. 1999, 4:252-7; Trip et al, Ann. Neurol. 25, 58: ; Fisher et al, Ophthalmol. 26, 113: ; Costello et al, Ann. Neurol. 26, 59: ) Optic Neuritis: Vision Loss Acute vision loss from inflammation and demyelination Improves when inflammation resolves Permanent vision loss from death of RGCs No improvement after inflammation NFL thinning correlates with decreased vision Optic Neuritis and MS MS is inflammatory demyelinating disease of CNS Histopathology of optic neuritis identical to brain and spinal cord lesions Neurological deficits relapse and remit with acute episodes of inflammation (most common) Axonal damage and loss of neurons also occurs, and correlates with permanent neurological disability Optic Neuritis and MS Treatment IV steroids hasten visual recovery No effect on final visual outcome Current MS therapies modulate inflammation At least 14 approved therapies Reduce incidence of acute episodes Limited effect on permanent disability Neuroprotective therapies needed to prevent permanent neurological disability (including vision loss) Injectable medications Avonex (interferon beta-1a) Betaseron (interferon beta-1b) Copaxone (glatiramer acetate) Extavia (interferon beta-1b) Glatopa (glatiramer acetate) Plegridy (peginterferon beta-1a) Rebif (interferon beta-1a) Zinbryta (daclizumab) Oral medications Aubagio (teriflunomide) Gilenya (fingolimod) Tecfidera (dimethyl fumarate) Infused medications Lemtrada (alemtuzumab) Novantrone (mitoxantrone) Tysabri (natalizumab) Studying Neuroprotection in Optic Neuritis: Why? How? Goal: Prevent permanent vision loss Means: Prevent RGC death Other important benefits: Potential neuroprotection for other MS lesions Identify candidate neuroprotective therapies for other neurodegenerative diseases Identify candidate neuroprotective therapies for other RGC diseases Glaucoma is slowly progressive, difficult to evaluate outcomes Short time frame of optic neuritis will allow shorter clinical trials with measureable vision and imaging parameters Methods: Use animal models of optic neuritis to identify drugs that prevent RGC loss Optic Neuritis in EAE Experimental autoimmune encephalomyelitis Most widely used animal models of MS Immunization with myelin proteins induces inflammation in brain, spine, and optic nerve similar to MS Inflammation Demyelination Axonal injury RGC loss 2

3 Vision Loss Detected by OKR in EAE Optic Neuritis Optic Neuritis in C57BL/6 EAE Mice Prusky et al, IOVS 24;197: Front Neurol 2:5 Optic nerve inflammation peaks by day 15 Vision loss progresses from day 15 3 RGC loss detectable by day 3, near complete by day 42 Mechanisms of RGC Loss in EAE Reactive oxygen species (ROS) mediate RGC loss in EAE optic neuritis Qi, et al (27) IOVS 48: Front Cell Neurosci 6:63 Methylprednisolone Treatment After Optic Neuritis Onset Does Not Block RGC Loss Control EAE + MP EAE mice treated with i.p. injection of PBS or 2 mg/kg methylprednisolone once daily. Methylprednisolone reduced EAE + PBS inflammation but did Do steroids suppress EAE optic neuritis? not prevent RGC Do therapies that reduce oxidative stress and/or increase loss. mitochondrial function suppress optic neuritis? IOVS 51:1439 Potential Neuroprotective Agents: Activators of SIRT1 Gene NAD-dependent deacetylase involved in cell stress responses and cell survival Regulate gene expression, promote increased lifespan Deacetylation of transcription factors, apoptosis proteins, structural proteins, mitochondrial regulators From Porcu and Chiarugi (25) TRENDS in Pharmacol. Sci. 26:94-13 Increase SIRT1 affinity for protein targets Resveratrol, a sirtuin activator found in red wine, prevents degradation of axotomized DRG neurons SIRT1 Activators ABC News From Sinclair D (25) Nature Genetics 37:

4 Resveratrol attenuates RGC loss in R/R EAE optic neuritis SRT51 is a pharmaceutical grade formulation of resveratrol Intravitreal SRT51 prevents RGC loss during optic neuritis SRT51 given intravitreally on d, 3, 7, 11 Oral SRT51 has similar effects, but requires very high dose RGC Number Placebo controls SRT51 controls * Placebo IOVS 48:362 6 µm SRT51 ** 13 µm SRT51 *** µm SRT51 1 RGC Number Oral Treatment Days 1-14 ** 1 N = 16 N = 22 N = Controls - vehicle Controls - 1 mg/kg SRT51 N = * 19 EAE w/on - vehicle EAE w/on - 1 mg/kg SRT51 J Neuro- Ophthalmol 3:328 SRT51 does not prevent inflammation Histology IOVS 48:362 J Neuro-Ophthalmol 3:328 cells/mouse cells/mouse Flow cytometry EAE - vehicle EAE - SRT51 EAE - vehicle EAE - SRT51 CD4+ CD11b+ CD45hi CD11b+ CD45hi IL-17+ IFNg+ Resveratrol Prevents RGC Loss in Chronic EAE Prevents almost all RGC loss No effect on inflammation Limited effect on vision Need to resolve inflammation SIRT1 Activators Reduce Oxidative Stress in Experimental Optic Neuritis Day 7 Day 3 Front Neurol 3:94 Acta Neuropathol Commun 2:3 SIRT1 Activator Neuroprotection SIRT1 activators prevent RGC loss during experimental optic neuritis Mechanism does not involve suppression of inflammation Mechanism involves reduction of oxidative stress Treatment of optic neuritis and MS with SIRT1 activators may provide added benefits to current immunomodulatory therapies Can other therapies also suppress inflammation and/or preserve vision? MP21 Prodrug of 2,4-dinitrophenol (DNP) Linker on hydroxyl group caps oxygen Enzymes cleave the linker after entry into vein Oxygen group protonated to active form DNP Mitochondrial uncoupling agent Uncoupling proteins can be induced by calorie restriction and exercise Promote neuronal cell stress responses Protect neurons via BDNF and other signaling pathways Preliminary studies suggest MP21 suppresses EAE Examined MP21 effects in EAE optic neuritis 4

5 MP21 Prevents RGC Loss Proof of concept pilot study: Induce EAE; Treat daily with MP21 after onset of optic neuritis MP21 Prevents Demyelination Treated daily beginning after onset of optic neuritis MP21 Preserves Vision Treated daily beginning after onset of optic neuritis MP21 Neuroprotection MP21 prevents RGC loss during experimental optic neuritis Reduces demyelination without suppressing inflammation Preserves visual function Known effects on mitochondria and oxidative stress suggest common mechanism of neuroprotection Phenolic compounds resveratrol and DNP both reduce RGC loss, with DNP also protecting vision Can combination therapies also suppress inflammation and preserve vision? ST266 A novel secretome from proprietary amnion cells Physiologic concentrations (pg/ml ng/ml) of biologic molecules, including growth factors and cytokines Intranasal delivery of ST266: Accumulates in optic nerve and vitreous Shown to be Anti-inflammatory in various models Neuroprotective alleviate neurite degeneration in vitro functional recovery in a rat TBI model Khan et al, Sci Rep 217;7:

6 Early intranasal ST266 treatment suppresses EAE optic neuritis Proof of concept pilot study: Induce EAE; Treatment Treat daily, one drop initiated before onset of optic (6 µl) ST266 or PBS neuritis Intranasal ST266 reduces RGC loss, axon degeneration, inflammation and demyelination Intranasal ST266 prevents loss of visual function OKR testing: Axon Staining Control EAE EAE+ST266 Khan et al, Sci Rep 217;7:41768 Khan et al, Sci Rep 217;7:41768 Late intranasal ST266 treatment suppresses/reverses EAE optic neuritis Treatment initiated after onset of optic neuritis Mechanism of ST266 Neuroprotection ST266 increases expression of SIRT1 SIRT1 inhibitors block ST266 neuroprotection in vitro Khan et al, Sci Rep 217;7:41768 Khan et al, Sci Rep 217;7:41768 ST266 Neuroprotection ST266 suppresses experimental optic neuritis Preserves and reverses vision loss Prevents RGC loss Decreases inflammation and demyelination Mechanism in part involves SIRT1 activation Intranasal delivery may provide a novel treatment strategy for optic nerve disease Conclusions Experimental optic neuritis in EAE is a useful model for examining neuroprotective therapies Therapies that prevent RGC loss in optic neuritis represent promising new treatments for MS, other optic neuropathies such as glaucoma, and other neurodegenerative diseases Focus on neuroprotective therapies that use common mechanisms of reducing oxidative stress may enhance translation to other diseases Specific studies of SIRT1 activators, mitochondrial uncoupling agents, and amnion fluid-based combination therapies warrant further investigation 6

7 Acknowledgments Collaborators: Noveome Larry Brown Howard Wessel IISER-Kolkata Jayasri Das Sarma Ashish Goyal Rahul Basu Subhajit Das Sarma Manmeet Singh Mitochon John Geisler TJU A. M. Rostami Elvira Ventura Yangtai Guan Philomela Tabuena Queens-Belfast Denise Fitzgerald Sirtris Peter Elliott Jim Ellis U Penn Reas Sulaimankutty Kimberly Dine Zoe Kelly Mayssa Nasrallah Mahasweta Dutt Mira Sachdeva Jean Bennett Daniel Chung Karen Revere Tonia Rex Gui-Shuang Ying Vivian Lee Thomas Quinn Catherine Callinan Wen Wu Ling Zuo Helayna Brown Esteban Luna Gabriela Grinblatt Bailey Baumann Lisa Lin Michael Lorentsen Funding provided by the NIH/NEI; RPB; and F. M. Kirby Foundation. MP21 was provided by Mitochon Pharmaceuticals, Inc. ST266 was provided by Noveome Biotherapeutics, Inc. Thank you! 7