Multiple Sclerosis (MS) and Neuromyelitis optica (NMO) are chronic inflammatory diseases of the central nervous system characterized by autoimmune attack of oligodendrocytes, demyelination of axons, and neurodegeneration. The two diseases share multiple symptoms, most notably a recurring optic neuritis that frequently results in monocular vision loss with MS and binocular loss with NMO. These recurring attacks can cause permanent vision loss due to apoptosis of retinal ganglion cells (RGCs), the axons of which comprise the optic nerve. The mechanisms underlying RGC death remain a major knowledge gap and as a result, there are currently no reliable treatments. Most NMO patients are seropositive for aquaporin-4 (AQP4) IgG, and multiple agents are currently being evaluated to treat AQP4-positive disease, but an estimated 12-25% of NMO patients are seronegative for AQP4. The goal of this application is to develop targeted therapeutics that mitigate optic neuritis for the susceptible MS and NMO patient populations whose disease is refractory to steroid therapy and/or is AQP4-negative. Our approach is to preserve RGC survival and vision by amplifying the capacity of RGCs and the immune cells that drive optic nerve demyelination and inflammation to neutralize free radical stress. This approach stems from the hypothesis that free radical stress is a major contributor to optic neuritis, and from our discovery that mice genetically ablated for Nrf2, the master anti-oxidant transcription factor, have an increased severity of visual deficits, RGC loss, and optic nerve inflammation in a mouse model of experimental autoimmune encephalomyelitis (EAE). This model reconstitutes key features of the optic neuritis observed in patients with MS and NMO, and we will explore two iterations of the model.
In Specific Aim 1, we will test if amplifying Nrf2 activity mitigates optic neuritis and vision loss in the Th1 adoptive transfer EAE model, which mimics MS optic neuritis.
In Specific Aim 2, we will test if amplifying Nrf2 activity mitigates optic neuritis and vision loss in the Th1 adoptive transfer EAE model, which is more representative of NMO. The therapeutics to be tested are novel Nrf2-expressing DNA nanoparticles (Nrf2-DNPs) that we developed and an FDA-approved pharmacological activator of Nrf2. The therapies will be tested individually or in combination and will be investigated for their capacity to prevent the onset of optic neuritis and to block recurrent episodes following the first attack. Therapeutic efficacy will be assessed in vivo by daily optokinetic tracking (OKT) to measure visual acuity and weekly diffusion-weighted and morphological MRI to correlate OKT changes with demyelination and inflammation. Additional analyses will be done to measure how effectively the therapeutics decrease RGC loss, inflammation/demyelination of the optic nerve, infiltration of specific immune cell types, an the extent of oxidative/nitrosative damage. The proposed studies have significant potential value from a therapeutic standpoint, and will reveal mechanistic insights into the contributions of free radical stress and damage to autoimmune demyelinating optic neuritis.
The goal of this application is to test therapeutic strategies for preventing and treating autoimmune demyelinating optic neuritis, the underlying cause of vision loss in patients with multiple sclerosis and neuromyelitis optica. Initial attacks of inflammation and demyelination cause visual deficits that are temporary but recurring bouts of optic neuritis can lead to permanent vision loss. The proposed studies test much-needed, vision-sparing therapeutic strategies focused on eliminating oxidative/nitrosative damage.
| Larabee, Chelsea M; Desai, Shruti; Agasing, Agnieshka et al. (2016) Loss of Nrf2 exacerbates the visual deficits and optic neuritis elicited by experimental autoimmune encephalomyelitis. Mol Vis 22:1503-1513 |
| Larabee, Chelsea M; Hu, Yang; Desai, Shruti et al. (2016) Myelin-specific Th17 cells induce severe relapsing optic neuritis with irreversible loss of retinal ganglion cells in C57BL/6 mice. Mol Vis 22:332-41 |
| Larabee, Chelsea M; Georgescu, Constantin; Wren, Jonathan D et al. (2015) Expression profiling of the ubiquitin conjugating enzyme UbcM2 in murine brain reveals modest age-dependent decreases in specific neurons. BMC Neurosci 16:76 |
