PDR-001 Alpha-Synuclein Removal PD Trial

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Overview

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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.

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Overview

Mermaid diagram (expand to render)

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["@tang2022"].

Trial Details

| Attribute | Value |
|-----------|-------|
| Phase | Phase 1 |
| Status | Recruiting |
| Sponsor | Ruijin Hospital (Shanghai, China) |
| NCT Number | [NCT07157345](https://clinicaltrials.gov/study/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) |

Mechanism of Action

The Challenge of Alpha-Synuclein Pathology

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[@masliah2010]
Progressive motor and non-motor symptoms

PDR-001: Targeted Protein Degradation

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

Preclinical Evidence

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

Trial Design

Study Type

Design: Single-group assignment, open-label
Primary Purpose: Treatment
Masking: None (open-label)

Treatment Arms

| Arm | Type | Description |
|-----|------|-------------|
| PDR-001 | Experimental | Single injection, 0.4 mL each side |

Primary Endpoints

Safety: PDR-001 treatment-related adverse events (assessed by CTCAE v5.0)

Timeframe: From enrollment to 52 weeks

2. Immunogenicity: Capsid neutralizing antibodies and binding antibodies against rAAV

Timeframe: From enrollment to 52 weeks

3. Vector Biodistribution: Titer of rAAV vectors in whole blood

Timeframe: From enrollment to 52 weeks

Secondary Endpoints

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

Eligibility Criteria

Inclusion Criteria

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

Exclusion Criteria

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

Clinical Significance

The PDR-001 trial represents several paradigm shifts in Parkinson's disease treatment:

Disease-Modifying Approach

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

Novel Delivery Strategy

Direct stereotactic injection to subthalamic nucleus
AAV9-mediated delivery ensures neuronal transduction
Localized treatment with potential for broader application

Precision Medicine

Specifically targets pathological alpha-synuclein
May preserve normal alpha-synuclein function
Potential for patient selection based on alpha-synuclein pathology burden

Challenges and Considerations

Technical Challenges

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

Regulatory Considerations

Novel mechanism requires careful safety monitoring
Gene therapy regulatory pathway
Potential for accelerated approval based on biomarker outcomes

Future Directions

Dose escalation studies
Expansion to earlier-stage PD patients
Combination with other disease-modifying approaches

[Alpha-Synuclein](/mechanisms/alpha-synuclein)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Gene Therapy for Neurodegeneration](/therapeutics/gene-therapy-neurodegeneration)
[AAV Vector Delivery](/therapeutics/aav-vector-delivery)
[Subthalamic Nucleus Deep Brain Stimulation](/therapeutics/deep-brain-stimulation-parkinsons)

External Links

[ClinicalTrials.gov - NCT07157345](https://clinicaltrials.gov/study/NCT07157345)
[Ruijin Hospital](https://www.rjh.com.cn/)
[PubMed - Alpha-synuclein research](https://pubmed.ncbi.nlm.nih.gov/)

References

[ClinicalTrials.gov, PDR-001 Study (2025)](https://clinicaltrials.gov/study/NCT07157345)

[Tang et al., Alpha-synuclein aggregation and Parkinson's disease (2022)](https://doi.org/10.1186/s40478-022-01401-w)

[Masliah et al., Molecular mechanisms of synaptic dysfunction in Alzheimer's disease (2010)](https://doi.org/10.1016/j.febslet.2010.03.012)

Pathway Diagram

The following diagram shows the key molecular relationships involving PDR-001 Alpha-Synuclein Removal PD Trial discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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PDR-001 Alpha-Synuclein Removal PD Trial

Overview

Overview

Trial Details

Mechanism of Action

The Challenge of Alpha-Synuclein Pathology

PDR-001: Targeted Protein Degradation

Preclinical Evidence

Trial Design

Study Type

Treatment Arms

Primary Endpoints

Secondary Endpoints

Eligibility Criteria

Inclusion Criteria

Exclusion Criteria

Clinical Significance

Disease-Modifying Approach

Novel Delivery Strategy

Precision Medicine

Challenges and Considerations

Technical Challenges

Regulatory Considerations

Future Directions

Related Pages

External Links

References

Pathway Diagram