Kynurenine pathway metabolite analysis for neurodegenerative disorder diagnostics and therapeutics

Overview

This research platform targets the kynurenine pathway (KP) as both a biomarker source and therapeutic intervention point for neurodegenerative disorders. The KP produces neurotoxic metabolites such as kynurenine (KYN), 3-hydroxykynurenine (3-OHKYN), and quinolinic acid (QA), as well as neuroprotective metabolites like picolinic acid (PA). An imbalance favoring neurotoxic metabolites has been linked to neuroinflammation and disease progression in multiple sclerosis, Alzheimer's disease, and Parkinson's disease.

The platform offers validated analytical methods and collaborative expertise for measuring KP metabolite concentrations in human biofluids, correlating these levels with inflammation markers, and testing small molecule inhibitors that modulate toxic metabolite production. Potential applications include biomarker discovery for early diagnosis, disease staging, and therapeutic drug development targeting KP enzymes.

Technical specifications

Validated analytical capabilities:

• Low-cost liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying nine KP metabolites
• Measurement of KP metabolites in plasma, cerebrospinal fluid (CSF), and urine
• Correlation analysis between peripheral and central KP metabolite levels
• Inflammation marker testing including C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-α)

Key metabolites analyzed:

• Neurotoxic: KYN, 3-OHKYN, 3-hydroxyanthranilic acid (3-OHAA), QA
• Neuroprotective: PA, tryptophan (TRP)
• Concentration ratios including KYN/TRP and PA/QA as disease indicators

Therapeutic testing capabilities:

• In vivo experiments using small molecule inhibitors (aspirin, 3-aminophenol, 3-aminosalicylic acid) as probes to control toxic metabolite production
• Drug screening assays targeting KP enzymes
• Sample collection protocols across early, mid, and late-stage disease progression

Demonstrated validation findings:

• CSF concentrations of KYN (26 ± 9 nM) and 3-OHKYN (5 ± 0.4 nM) correlated with plasma levels (41 and 5 times higher respectively)
• Four KP analytes (KYN, 3-OHKYN, 3-OHAA, TRP) showed significant correlations between CSF and plasma at time t2
• KYN/TRP ratio in CSF showed positive correlation with plasma concentrations

Technology readiness level

Current status: validated analytical method with demonstrated correlations between CSF and plasma KP metabolite levels in 17 human subjects. Published collaborative research with biochemist and clinician partners has established baseline methodology.

Planned next-stage validation:

• Recruitment of 48 healthy volunteers for comprehensive KP metabolite profiling across plasma, CSF, and urine
• Expanded sampling in three disease groups (multiple sclerosis, Parkinson's, Alzheimer's) across early, mid, and late-stage progression
• Development of therapeutic drug testing partnerships using KP enzyme inhibitors
• In vivo inhibitor assays to validate therapeutic targets

The research is positioned at the translational stage, bridging analytical method validation with clinical biomarker discovery and therapeutic target development. Human subject samples are sourced through Atlanta-area health centers, with one-year projected timelines for initial cohort studies.