The PDR-001 trial is a first-in-human Phase 1 clinical study evaluating a novel gene therapy approach for Parkinson's disease that directly targets the pathological aggregation of alpha-synuclein. Unlike conventional symptomatic treatments, PDR-001 aims to modify the underlying disease process by delivering a peptide that promotes targeted degradation of alpha-synuclein aggregates in the brain.
This trial represents a significant advancement in Parkinson's disease therapeutics, as it addresses the root cause of dopaminergic neuron death rather than merely managing symptoms.
| Attribute |
Value |
| Phase |
Phase 1 |
| Status |
Recruiting |
| Sponsor |
Ruijin Hospital (Shanghai, China) |
| NCT Number |
NCT07157345 |
| Intervention |
PDR-001 (AAV9-packaged tat-βsyn-deg peptide) |
| Delivery Method |
Bilateral stereotactic injection into subthalamic nucleus (STN) |
| Enrollment |
12 patients (estimated) |
| Duration |
52 weeks |
| Location |
Ruijin Hospital, Shanghai, China |
| Start Date |
October 2025 (estimated) |
| Completion Date |
December 2029 (estimated) |
Parkinson's disease is characterized by the pathological aggregation of alpha-synuclein protein into Lewy bodies and Lewy neurites within dopaminergic neurons. This aggregation leads to:
- Progressive loss of dopaminergic neurons in the substantia nigra
- Disruption of neuronal function and synaptic transmission
- Progressive motor and non-motor symptoms
PDR-001 (tat-βsyn-deg) is a three-segment peptide designed to selectively target alpha-synuclein for degradation:
- Tat Transduction Domain: Enables cellular uptake and trafficking to the brain
- Beta-synuclein Binding Domain: Specifically binds to alpha-synuclein
- Degradation Tag: Promotes ubiquitin-proteasome-mediated clearance
When packaged into AAV9 capsids and delivered via bilateral stereotactic injection into the subthalamic nucleus, PDR-001 has demonstrated:
- Efficient transduction of target neurons
- Reduction of alpha-synuclein aggregates in the target region
- Marked improvements in motor deficits in preclinical models
Studies in both human-alpha-synuclein-expressing mice and non-human primate models of PD have shown:
- Robust alpha-synuclein clearance in treated brain regions
- Significant improvement in motor performance
- Good safety profile in animal models
- Design: Single-group assignment, open-label
- Primary Purpose: Treatment
- Masking: None (open-label)
| Arm |
Type |
Description |
| PDR-001 |
Experimental |
Single injection, 0.4 mL each side |
- Safety: PDR-001 treatment-related adverse events (assessed by CTCAE v5.0)
- Timeframe: From enrollment to 52 weeks
- Immunogenicity: Capsid neutralizing antibodies and binding antibodies against rAAV
- Timeframe: From enrollment to 52 weeks
- Vector Biodistribution: Titer of rAAV vectors in whole blood
- Timeframe: From enrollment to 52 weeks
- Levodopa Equivalent Daily Dose (LEDD): Changes in antiparkinsonian medication requirements
- MDS-UPDRS: Movement Disorder Society - Unified Parkinson's Disease Rating Scale
- PGI-I: Patient Global Impression - Improvement scale
- CGI-I: Clinical Global Impression - Improvement scale
- MMSE: Mini-Mental State Examination (cognitive function)
- HAM-D: Hamilton Depression Rating Scale (17-item)
- HAM-A: Hamilton Anxiety Rating Scale
- PDSS-2: Parkinson's Disease Sleep Scale-2
- Clinically confirmed diagnosis of primary PD (according to 2016 Chinese Diagnostic Criteria or 2015 MDS criteria)
- Age 40-65 years (inclusive) at screening
- Disease duration ≤ 5 years
- Hoehn & Yahr stage ≤ 2 in the "off" state
- Atypical or secondary parkinsonian syndromes (Parkinson-plus, hereditary parkinsonism, drug-induced)
- Contra-indications to intracranial surgery or prior neurosurgical procedures (DBS, pallidotomy, etc.)
- Structural brain abnormalities, vascular malformations, intracranial tumors, or risk of intracranial hemorrhage
- MMSE score < 24 (cognitive impairment)
- PHQ-9 score ≥ 16 (major depression)
- Abnormal hepatic or renal function (AST/ALT > 1.5× ULN, or serum creatinine > 1.5× ULN)
- Coagulation disorders or current anticoagulant use
- Positive screening for infectious diseases (Hepatitis B, C, HIV, syphilis)
- Current antiviral therapy for hepatitis B or C
The PDR-001 trial represents several paradigm shifts in Parkinson's disease treatment:
- Targets the root cause of PD (alpha-synuclein pathology) rather than symptoms
- Potential to slow or prevent disease progression
- First-in-human validation of peptide-mediated protein degradation
- Direct stereotactic injection to subthalamic nucleus
- AAV9-mediated delivery ensures neuronal transduction
- Localized treatment with potential for broader application
- Specifically targets pathological alpha-synuclein
- May preserve normal alpha-synuclein function
- Potential for patient selection based on alpha-synuclein pathology burden
¶ Challenges and Considerations
- Ensuring adequate distribution of AAV9 vectors in target brain region
- Balancing efficacy with safety in first-in-human study
- Long-term durability of treatment effect
- Novel mechanism requires careful safety monitoring
- Gene therapy regulatory pathway
- Potential for accelerated approval based on biomarker outcomes
- Dose escalation studies
- Expansion to earlier-stage PD patients
- Combination with other disease-modifying approaches