Metabolic programming therapy for resolving pathogenic inflammation in multiple sclerosis

Overview

This solution offers a new therapeutic strategy for multiple sclerosis (MS) that reprograms immune cells from a pathogenic inflammatory state back to immune homeostasis. The approach leverages the enzyme indoleamine 2,3-dioxygenase 1 (IDO), which catabolizes the essential amino acid tryptophan into kynurenine, a metabolite that activates the aryl hydrocarbon receptor (AhR) and promotes immune regulation.

Two delivery formats are being developed. Systemic PEG-IDO is designed to reprogram circulating immune cells before they traffic to the central nervous system (CNS). A localized fusion protein, IDO-galectin-3 (IDO-Gal3), binds to abundant tissue glycans to restrict diffusion and concentrate IDO activity at targeted inflamed tissues. In preclinical studies, retro-orbital injection of IDO-Gal3 crosses the leaky blood-brain barrier in inflamed CNS, similar to how intrathecal administration delivers therapies such as rituximab and baclofen in MS patients.

The therapeutic addresses a critical unmet need by reducing pathogenic Th17 CD4+ T cells in the CNS, increasing regulatory T cell (Treg) frequency, and reversing hind limb paralysis in validated MS mouse models without observed neurotoxicity.

Technical specifications

Mechanism of action:

• IDO catabolizes tryptophan into kynurenine, activating AhR signaling in Tregs and other immune cells
• AhR activation promotes immune suppression and CNS protection
• The approach targets both immune populations and neuroprotective pathways, including AhR activation in astrocytes, similar to the mechanism of the oral MS drug candidate laquinimod

Delivery formats:

• PEG-IDO (systemic): Intraperitoneal injection reprograms circulating immune cells trafficking to the CNS
• IDO-Gal3 (localized): Fusion protein with galectin-3 binds tissue glycans to restrict diffusion and localize IDO activity in inflamed tissue; delivered via retro-orbital injection across the leaky blood-brain barrier

Key preclinical findings:

• Single-dose treatment at peak disease (clinical score 2.5–3) reverses hind limb paralysis in C57BL/6 EAE mice
• Treated mice recover to a final score of 1 (flaccid tail) with fewer CNS lesions
• Both formulations reduce pathogenic Th17 CD4+ T cells in the CNS
• PEG-IDO additionally increases Treg cell frequency with a more stable phenotype
• No toxicity observed in lung, heart, liver, kidney, or small intestine following repeated dosing
• No impact on clearance of Listeria monocytogenes, suggesting the therapy is not globally immunosuppressive

Technology readiness level

This technology is currently at the preclinical validation stage. Preliminary efficacy and safety data have been generated in the C57BL/6 chronic non-relapsing EAE mouse model, with demonstrated disease reversal, reduced CNS lesions, and no observed toxicity.

Future validation plans include expanded testing in three EAE models: a chronic non-relapsing model in C57BL/6 mice, a relapsing-remitting model in SJL mice, and a B cell-dependent EAE model. Studies will evaluate both disease prevention (at onset) and therapeutic intervention (at peak disease), along with detailed immunological mechanism studies and dose-escalation toxicology assessments. The approach builds on recent published findings and aims to establish dosing regimens for advancing toward clinical translation.