THERAPEUTIC INHIBITION OF THE INTEGRATED STRESS RESPONSE RESTORES VISUAL FUNCTION IN A PRECLINICAL MULTIPLE SCLEROSIS MOUSE MODEL

Multiple Sclerosis (MS) is an inflammatory demyelinating disease that, despite disease-modifying therapies, causes progressive neurological decline. The visual pathway is often affected early, making it a relevant system for MS study. Our lab showed that loss of retinal ganglion cell (RGC) synapses impairs visual circuit function before detectable RGC demyelination or neuroaxonal loss. However, regulatory processes remain largely elusive. The integrated stress response (ISR), a cytoprotective pathway upregulated in MS, is a promising target for neuronal protection, as prophylactic ISR inhibition in MS models improves RGC survival and visual function at peak disease. Nevertheless, it remains unknown whether ISR modulation benefits early synaptic pathology and if benefits persist when treatment occurs after disease onset. To address this, we inhibited or prolonged the ISR using small molecules in a clinically relevant therapeutic approach following disease onset in the MS-relevant experimental autoimmune encephalomyelitis (EAE) model. Comprehensive functional and postmortem analyses revealed that therapeutically timed ISR inhibition, but not prolongation, after the onset of clinical symptoms (visual impairment and tail and hindlimb paralysis) restored visual function in EAE mice, while spinal cord-driven paralysis appeared relatively unaffected. Ongoing work is evaluating drivers of these effects, focusing on alterations in synaptic, neuroaxonal, and myelin integrity. Together, these data suggest that ISR inhibition after disease onset can restore visual function, offering new avenues for promoting visual circuit restoration in MS. This work may guide treatment strategies beyond MS, including other neurodegenerative diseases such as Alzheimer’s disease, in which ISR induction is a prominent pathological feature.