MOG Antibody-Associated Disorder

The vast majority of EAE models used in MS and neuroimmunology research are driven primarily by activated CD4+ T cells reactive to myelin antigens. While these models replicate many features of T cell-mediated demyelination, they do not faithfully model the humoral immune component that is central to MOGAD and, to a significant extent, to MS itself (where B cells and antibody contributions are recognised as disease-modifying targets). MOGAD is defined by pathogenic MOG-IgG, and B cell-depleting therapies (rituximab, ocrelizumab) are among the most effective therapeutic approaches. Without animal models that explicitly include B cell participation and MOG antibody generation, the preclinical evaluation of these therapies lacks mechanistic validity.

Measuring functional visual consequences in these B cell-inclusive models requires an endpoint that is sensitive to optic nerve demyelination and retinal ganglion cell loss, can be applied longitudinally without surgery or terminal procedures, and is sufficiently dynamic to capture both the acute inflammatory phase and subsequent recovery or further decline. For the optic neuritis endpoint specifically, the optomotor reflex provides a direct, retina-to-brainstem subcortical readout that is unaffected by the level of motor disability present in EAE animals – a critical confound when interpreting limb-score-based disease severity measures in models with concurrent spinal cord inflammation.

MOGAD and NMOSD are now recognised as distinct from MS in their pathophysiology, prognosis, and treatment response. However, most preclinical demyelinating disease research relies on the classical MOG_35-55 EAE model, which primarily models T cell-mediated MS-like disease. The challenge for MOGAD researchers is two-fold: first, to develop or select EAE variants that more faithfully recapitulate MOGAD immunopathology; and second, to demonstrate that these models produce measurable and distinct visual pathway dysfunction that reflects the clinical features of MOGAD optic neuritis (severe bilateral involvement, optic disc oedema, and the risk of progressive axon degeneration with recurrent bouts).

Axon degeneration in the optic nerve – a hallmark of progressive visual disability in relapsing MOGAD – is not adequately captured by conventional EAE clinical scoring or acute pathology measures alone. A longitudinal, functional visual endpoint is needed to detect the transition from inflammatory demyelination to axon loss-driven irreversible functional decline. For a focused treatment of axon degeneration mechanisms and their visual consequences, see Axon Degeneration. For the broader EAE model landscape, see Experimental Autoimmune Encephalomyelitis.

Because MOGAD is defined by pathogenic MOG-IgG, reducing circulating antibody titres is a rationally targeted therapeutic strategy. The neonatal Fc receptor (FcRn) normally recycles IgG from lysosomal degradation back into circulation, thus maintaining serum IgG levels. FcRn blockade has entered clinical development (efgartigimod, rozanolixizumab) as a pan-IgG-lowering approach for antibody-mediated diseases including myasthenia gravis and CIDP, and represents a disease-mechanism-appropriate candidate for MOGAD. However, preclinical demonstration that FcRn-mediated IgG reduction translates specifically to preserved visual function – the primary clinical outcome in MOGAD – was absent until the Remlinger et al. (2022) study.

A key challenge in this type of study is selecting a functional endpoint that is sensitive to optic nerve damage, longitudinally repeatable (to capture treatment-related changes over the disease course), and not confounded by the motor disability that complicates interpretation in animals with concurrent spinal cord EAE. OptoDrum addresses all three requirements, providing the optomotor reflex endpoint that isolates retino-brainstem pathway integrity from lower-body motor dysfunction. This is particularly important in EAE models where clinical disability scoring predominantly reflects spinal cord involvement rather than visual pathway damage.

In clinical MOGAD, treatment decisions are distinct from those in MS and NMOSD: disease-modifying therapies approved for MS (natalizumab, dimethyl fumarate, fingolimod) are not indicated and may even worsen MOGAD, while high-dose intravenous methylprednisolone, IVIG, rituximab, and tocilizumab (an IL-6 receptor antagonist) are the current mainstays (Gklinos and Dobson, Antibodies, 2024). Translational preclinical studies therefore need to use MOGAD-specific models, not generic EAE, and to validate functional visual endpoints that map to the clinically relevant outcome of optic neuritis severity and visual recovery.

The risk of conflating MOGAD with MS in preclinical research is substantial: both diseases produce optic neuritis and demyelination, and both are studied using MOG-peptide EAE models. However, the 2023 international diagnostic criteria (Banwell et al., Lancet Neurol., 2023) explicitly require exclusion of MS as a condition of MOGAD diagnosis, reflecting the fundamental mechanistic distinctions between the two diseases. In MS, demyelination is driven primarily by CD8+ and CD4+ T cells targeting multiple myelin antigens, with a chronic neurodegenerative course and permanent disability accumulation. In MOGAD, the pathology is defined by MOG-IgG with CD4-dominant perivascular infiltration, a perivenous demyelination pattern, and generally more reversible lesions – though cumulative optic nerve damage from relapsing bouts remains the chief disability driver.

The translational implication is that MOG-peptide EAE (MOG_35-55) is a T cell-mediated model that most closely approximates MS pathophysiology, not MOGAD (Capper et al., J. Neuroinflammation, 2025). MOGAD research requires models that explicitly incorporate MOG-IgG or B cell-dependent humoral pathology. This distinction is not merely academic: therapies that suppress T cell traffic (natalizumab) or T cell activation (glatiramer acetate, dimethyl fumarate) may have minimal or even detrimental effects in MOGAD, while B cell depletion (rituximab) and IL-6 pathway blockade (tocilizumab) have emerged as the most promising preventive strategies for relapsing disease (Gklinos and Dobson, Antibodies, 2024). For broader comparative context on MS-relevant models, see Multiple Sclerosis.

Disability accrual in MOGAD is predominantly driven by repeated optic neuritis bouts, each of which carries a risk of axon loss that does not fully recover even when acute inflammatory oedema resolves. A single episode of MOGAD optic neuritis leaves on average a greater degree of retinal nerve fibre layer thinning and persistent optomotor deficit than a single episode of MS-associated optic neuritis. Longitudinal functional visual measurement across multiple induced bouts – capturing residual deficit, recovery fraction, and cumulative decline – is therefore the most clinically relevant preclinical readout for MOGAD relapse-prevention therapy development.

Age at onset is a major determinant of MOGAD phenotype and prognosis. Children, especially those with ADEM as the presenting event, frequently have transient MOG-IgG seropositivity and a monophasic course with good recovery. Adults are more likely to maintain persistent MOG-IgG seropositivity and experience multiple relapses, predominantly as optic neuritis, with the risk of cumulative visual disability (Misu et al., Clin. Exp. Neuroimmunol., 2023; Gklinos and Dobson, Antibodies, 2024). Approximately 30-50% of adult MOGAD patients experience a relapsing course, and relapses are almost exclusively optic neuritis in this subgroup.

Standard single-immunisation EAE protocols model an acute monophasic disease course. Modelling the relapsing-remitting pattern of adult MOGAD – characterised by repeated episodes of optic neuritis with incomplete visual recovery – requires either repeated MOG-IgG augmentation protocols or spontaneously relapsing models. The functional visual readout must therefore be capable of documenting: (a) the acute visual decline at each bout onset; (b) the recovery fraction between bouts; and (c) the residual cumulative deficit. OptoDrum’s capacity for repeated daily measurement without animal training, surgical preparation, or restraint-induced stress makes it uniquely suited to capture this multi-episode kinetic profile.