| Attribute |
Value |
| Study Type |
Preclinical + Clinical Biomarker |
| Duration |
36 months |
| Phase |
Proof-of-Concept |
| Primary Endpoint |
CSF 8-oxoG correlation with disease progression |
| Secondary Endpoints |
PARP activity, DNA repair enzyme levels |
Impaired DNA damage repair capacity in dopaminergic neurons drives neurodegeneration in Parkinson's disease. Targeting this pathway — via PARP inhibition, NAD+ augmentation, or DNA repair enhancement — will slow disease progression.
Experiment 1: DNA Damage Assessment in Patient-Derived Neurons
- Cell lines: iPSC-derived dopaminergic neurons from:
- PD patients (LRRK2 G2019S, GBA N370S, idiopathic)
- Healthy controls
- Ataxia-telangiectasia (ATM±) carriers (positive control)
- Assays:
- Comet assay (alkaline) for total DNA damage
- 8-oxoG immunostaining quantification
- γH2AX foci counting (DSB marker)
- OGG1 activity measurement
- Sample size: 15 lines per group
Experiment 2: PARP1 Activation Kinetics
- Method: Live-cell imaging with PARylation sensor
- Stimuli: Hydrogen peroxide (100µM), rotenone (1µM), MPTP (10µM)
- Readouts: PARylation kinetics, NAD+ depletion rate, cell viability
- Inhibitor arm: Olaparib (10µM), rucaparib (5µM)
Experiment 3: DNA Repair Capacity Ex Vivo
- Patient samples: Peripheral blood mononuclear cells (PBMCs)
- Tests:
- Base excision repair assay (BER)
- Nucleotide excision repair assay (NER)
- DNA damage sensitivity to UV, oxidative stress
- Correlation: With age of onset, disease severity (MDS-UPDRS)
Experiment 4: Mouse Model Characterization
- Model: MitoPark mice (mitochondrial complex I deficiency)
- Assessments:
- 8-oxoG levels in substantia nigra (IHC)
- PARP1 activation (Western blot)
- OGG1 expression (qPCR, IHC)
- Behavioral testing (rotarod, cylinder, gait analysis)
- Intervention arm:
- Olaparib (50mg/kg daily, i.p.)
- Nicotinamide riboside (500mg/kg daily, oral)
- Cohort: 100 early-stage PD (H&Y 1-2), 50 healthy controls
- Samples:
- CSF (8-oxoG, PAR, NAD+)
- Serum (PARP activity, inflammatory markers)
- PBMCs (DNA repair capacity ex vivo)
- Follow-up: Baseline, 6, 12, 24, 36 months
- Endpoints:
- Correlation with MDS-UPDRS progression
- Correlation with DAT-SPECT imaging
- Biomarker predictive value for progression
- Age 40-75 years
- Diagnosis: PD (UK Brain Bank criteria)
- Hoehn & Yahr stage 1-2
- Disease duration < 5 years
- No DBS or advanced therapy
- No significant cognitive impairment (MoCA > 24)
- Secondary parkinsonism
- Active infection or inflammatory disease
- Cancer history (5 years)
- DNA repair disorder (Ataxia-telangiectasia, etc.)
- Previous PCR/chemotherapy
- CSF 8-oxoG level — correlation with 24-month MDS-UPDRS change
- PARP activity — correlation with disease severity
- DNA repair capacity (PBMC) — correlation with age of onset
- Serum NAD+ levels — correlation with cognitive function
- DAT-SPECT progression — correlation with biomarkers
- Telomere length — correlation with biomarker levels
- Mitochondrial DNA copy number — in CSF cells
- Sample size calculation: Power 80%, α=0.05, effect size 0.5
- Primary analysis: Mixed-effects model for biomarker-disease progression
- Multiple comparisons correction: FDR (Benjamini-Hochberg)
- Machine learning: Random forest for biomarker combination prediction
| Item |
Cost (USD) |
| iPSC differentiation |
$150,000 |
| Animal studies |
$200,000 |
| Clinical cohort (100 PD, 50 controls) |
$350,000 |
| Biomarker assays |
$100,000 |
| Personnel (2 FTE × 3 years) |
$450,000 |
| Total |
$1,250,000 |
| Risk |
Mitigation |
| Insufficient patient recruitment |
Multi-center consortium |
| Biomarker variability |
Standardized collection protocol |
| PARP inhibitor toxicity |
Low-dose escalation design |
| iPSC line variability |
Isogenic controls where possible |
- Validation of hypothesis: Strong correlation between DNA damage markers and PD progression
- Biomarker qualification: 8-oxoG/PAR as progression markers
- Target validation: PARP inhibitor benefit in biomarker-high patients
- Foundation for trial: Phase IIa study design parameters
- Month 1-6: iPSC characterization, assay development
- Month 6-18: Preclinical interventions
- Month 12-24: Clinical cohort enrollment
- Month 24-36: Follow-up completion, analysis
- Month 36: Primary results, publication
DNA damage repair deficiency is implicated across neurodegenerative diseases: