GGC Glutathione PD NCT07064005
Trial Overview
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clinical_trials_ggc__1["Scientific Rationale"]
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clinical_trials_ggc__2["Glutathione: The Brains Master Antioxidant"]
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clinical_trials_ggc__3["Glutathione Depletion in Parkinsons Disease"]
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clinical_trials_ggc__4["The GGC Gamma-Glutamylcysteine Approach"]
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clinical_trials_ggc__5["Trial Objectives"]
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...GGC Glutathione PD NCT07064005
Trial Overview
Mermaid diagram (expand to render)
| 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:
Redox regulation: Maintaining the cellular redox balance
Detoxification: Conjugating and eliminating toxic metabolites
Mitochondrial protection: Preserving mitochondrial function
Neuroinflammation modulation: Reducing pro-inflammatory signalingGlutathione 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
The loss of GSH in PD is thought to occur through multiple mechanisms:
- 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
Brain GSH Enrichment: Evaluate enrichment of master antioxidant glutathione (GSH) levels in brain and blood of PD patients compared to baseline due to GGC supplementation
Motor Function Assessment: Study changes in motor function in PD patients due to GGC oral supplementation
Cognitive Assessment: Evaluate cognitive skills pre and post GGC supplementation
Gut Health: Study impact of GGC on gut health in PD patientsSecondary Objectives
Motor function monitoring using MDS-UPDRS
Cognitive function modulation using RBANS
Psychological distress assessment using BSI-18
Cognitive abilities self-report using PROMIS Cognitive Function
Attention/processing speed assessment using Trail Making Test A&BTrial 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
MEGA-PRESS is a non-invasive imaging technique that detects various neurochemicals, including glutathione, using proton (¹H) MR spectroscopy [3](https://pubmed.ncbi.nlm.nih.gov/).
Eligibility Criteria
Inclusion Criteria
Confirmed Parkinson's Disease diagnosis (UK Brain Bank criteria)
Montreal Cognitive Assessment (MoCA) ≥ 26
Age 50-80 years
Ability to read and write in EnglishExclusion Criteria
MRI contraindications:
- Pacemakers
- Aneurysm clips
- Artificial heart valves
- Ear implants
- Metal fragments in eyes, skin, or body
- Claustrophobia
Neurological conditions:
- Parkinson's disease dementia
- Dementia with Lewy bodies
- Previous traumatic head injury
Medical conditions:
- History of cancer
- Active psychosis or delirium
- Chronic kidney disease (creatinine > 1.5 mg/dL)
- Liver disease (AST/ALT ≥ 1.5 × ULN)
Medication exclusions:
- 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:
High metabolic demand: Dopaminergic neurons have high oxygen consumption
Iron accumulation: Elevated iron in SNc catalyzes ROS generation
MAOx activity: Monoamine oxidase produces H₂O₂ as a byproduct
Mitochondrial dysfunction: Complex I deficiency increases ROS
Glutathione depletion: Reduced antioxidant capacityThe combination of elevated oxidative stress and diminished antioxidant capacity creates a "perfect storm" that drives neurodegeneration.
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
Iron catalyzes the Fenton reaction, producing highly reactive hydroxyl radicals:
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:
Root cause mitigation: Addressing fundamental oxidative stress
Neuroprotection: Preserving remaining dopaminergic neurons
Progression modification: Potentially slowing disease advancementAdvantages 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
[Dias et al., The role of oxidative stress in Parkinson's disease (2013)](https://pubmed.ncbi.nlm.nih.gov/24252804/)
[Shukla et al., Glutathione Depletion in PD - MR Spectroscopy Study (2023)](https://pubmed.ncbi.nlm.nih.gov/)
[Mandal et al., Quantitation of Brain and Blood Glutathione and Iron (2023)](https://pubmed.ncbi.nlm.nih.gov/37257017/)
[ClinicalTrials.gov - NCT07064005](https://clinicaltrials.gov/study/NCT07064005)
[University of Pittsburgh - Mandal Lab](https://www.pitt.edu/)
Page updated: 2026-03-27