GGC/Glutathione Antioxidant Enrichment for Parkinson's Disease (NCT07064005)

GGC Glutathione PD NCT07064005

Trial Overview

GGC Glutathione PD NCT07064005

Trial Overview

| Field | Value |
|-------|-------|
| NCT Number | NCT07064005 |
| Status | Enrolling by Invitation |
| Phase | Phase 1 |
| Sponsor | Pravat Mandal, PhD (University of Pittsburgh) |
| Collaborators | Waste Connections Inc |
| Study Type | Interventional |
| Intervention | Gamma-glutamylcysteine (GGC) 400mg orally, twice daily |
| Target Enrollment | 12 patients |
| Study Duration | 12 months |
| Location | UPMC Presbyterian Hospital, Pittsburgh, PA, United States |
| Acronym | PDGSH |

Scientific Rationale

Glutathione: The Brain's Master Antioxidant

Glutathione (GSH) is the most abundant endogenous antioxidant in the brain, playing a critical role in protecting neurons from oxidative damage [1](https://pubmed.ncbi.nlm.nih.gov/). It serves multiple essential functions:

Glutathione Depletion in Parkinson's Disease

A landmark finding in PD research is the significant depletion of glutathione in the substantia nigra pars compacta (SNc) [2](https://pubmed.ncbi.nlm.nih.gov/). This depletion:

• Is present in early-stage PD, even before symptom onset
• Renders dopaminergic neurons particularly vulnerable to oxidative stress
• Contributes to mitochondrial dysfunction
• Promotes alpha-synuclein aggregation
• Accelerates neurodegeneration

• Reduced synthesis: Impaired gamma-glutamylcysteine synthetase activity
• Increased consumption: Elevated oxidative stress demands
• Transport deficits: Altered GSH transport across the blood-brain barrier

The GGC (Gamma-Glutamylcysteine) Approach

Gamma-glutamylcysteine (GGC) is a dipeptide precursor to glutathione that:

• Crosses the blood-brain barrier more efficiently than GSH itself
• Provides substrate for endogenous GSH synthesis
• Bypasses the rate-limiting step in GSH production (gamma-glutamylcysteine synthetase)
• Has demonstrated safety in preclinical and clinical studies

Trial Objectives

Primary Objectives

Secondary Objectives

Trial Design

Study Protocol

This is a single-arm, open-label pilot trial. Each patient will undergo:

| Assessment | Timing |
|------------|--------|
| Baseline MRI/MRS | Day 0 |
| Blood GSH/Iron | Day 0 |
| Neuropsychological testing | Day 0 |
| GGC supplementation starts | Day 1 |
| 12-month follow-up | MRI/MRS, blood tests, cognitive testing |

Intervention Details

Drug: Gamma-glutamylcysteine (GGC)

• Dose: 400 mg orally, twice daily (morning and afternoon)
• Duration: 12 months
• Administration: Oral tablets

Imaging Parameters

Magnetic Resonance Spectroscopy (MRS):

• Technique: MEGA-PRESS pulse sequence
• Target metabolites: Glutathione, iron
• Brain regions: Substantia nigra, frontal cortex

Eligibility Criteria

Inclusion Criteria

Exclusion Criteria

• Pacemakers
• Aneurysm clips
• Artificial heart valves
• Ear implants
• Metal fragments in eyes, skin, or body
• Claustrophobia

• Parkinson's disease dementia
• Dementia with Lewy bodies
• Previous traumatic head injury

• History of cancer
• Active psychosis or delirium
• Chronic kidney disease (creatinine > 1.5 mg/dL)
• Liver disease (AST/ALT ≥ 1.5 × ULN)

• Antioxidant therapy (ashwagandha, ginkgo biloba, N-acetylcysteine)
• Illicit drug abuse/dependence (cocaine, heroin, marijuana, fentanyl)

Outcome Measures

Primary Outcomes

| Measure | Description | Timeframe |
|---------|-------------|-----------|
| Brain GSH levels | Change in brain glutathione (mM) using MRS | 12 months |
| Brain iron levels | Change in brain iron (ppb) using MRI | 12 months |
| Blood iron levels | Change in baseline blood iron (ng/μl) | 12 months |
| Blood GSH levels | Change in baseline blood glutathione (μmol/l) | 12 months |

Secondary Outcomes

| Measure | Scale/Instrument | Timeframe |
|---------|-----------------|-----------|
| Motor function | MDS-UPDRS (0-176 scale) | 12 months |
| Cognitive function | RBANS | 12 months |
| Psychological distress | BSI-18 | 12 months |
| Self-reported cognition | PROMIS Cognitive Function (8-40) | 12 months |
| Executive function | Trail Making Test A&B | 12 months |

Scientific Background

Oxidative Stress in Parkinson's Disease

The substantia nigra in PD faces unique challenges regarding oxidative stress:

The combination of elevated oxidative stress and diminished antioxidant capacity creates a "perfect storm" that drives neurodegeneration.

Glutathione Metabolism Pathway

Glutathione synthesis occurs through a two-step process:

Glutamate + Cysteine → γ-Glutamylcysteine (γ-GCS) → Glutathione (GSH)
(rate-limiting) (GSH synthetase)

The rate-limiting step is catalyzed by γ-glutamylcysteine synthetase (γ-GCS). By providing GGC directly, this trial aims to bypass rate-limiting constraints and boost GSH production.

Iron Homeostasis in PD

Brain iron dysregulation is a hallmark of PD:

• Elevated iron in the substantia nigra
• Ferritin dysfunction: Impaired iron storage
• Transferrin changes: Altered iron transport

Fe²⁺ + H₂O₂ → Fe³⁺ + •OH + OH⁻

GSH helps neutralize these reactive species and maintain iron homeostasis.

Clinical Significance

Disease-Modifying Potential

This trial represents a disease-modifying approach that targets:

Advantages of GGC Approach

| Feature | Benefit |
|---------|---------|
| Oral administration | Non-invasive, patient-friendly |
| BBB penetration | Direct CNS delivery |
| Precursor mechanism | Physiological GSH elevation |
| Long-term use | 12-month supplementation |
| Multimodal outcomes | Comprehensive efficacy assessment |

Comparison with Other Antioxidant Approaches

| Intervention | Mechanism | Status | Limitations |
|-------------|-----------|--------|-------------|
| CoQ10 | Mitochondrial antioxidant | Mixed results | Poor BBB penetration |
| Vitamin E | Lipid antioxidant | Ineffective | Pro-oxidant at high doses |
| NAC | GSH precursor | Limited efficacy | Poor CNS uptake |
| GGC | Direct GSH precursor | This trial | Ongoing |

Cross-References

• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Glutathione Metabolism](/mechanisms/glutathione-metabolism)
• [Oxidative Stress in PD](/mechanisms/oxidative-stress)
• [Neuroprotective Therapies](/therapeutics/neuroprotection)
• [DJ-1/PARK7 Oxidative Stress Pathway](/mechanisms/dj1-oxidative-stress-pathway-parkinsons)
• [Iron Metabolism in Neurodegeneration](/mechanisms/iron-metabolism-neurodegeneration)
• [Mitochondrial Dysfunction in PD](/mechanisms/mitochondrial-dysfunction-parkinsons)

Research Team

| Investigator | Role | Affiliation |
|--------------|------|-------------|
| Pravat K. Mandal, PhD | Principal Investigator | University of Pittsburgh |

References