Testing if PDR-001 Can Safely and Effectively Remove Harmful Brain Protein in Parkinson's Disease

Official title

A Study on the Safety, Tolerability, and Efficacy of PDR-001 Injection for Bilateral Stereotactic Subthalamic Nucleus (STN) Clearance of α-synuclein

Overview

Parkinson's disease (PD) poses a severe threat to human health, and its incidence is rising year by year. Current therapeutic options are limited by significant shortcomings. Pathological aggregation of α-synuclein and the consequent death of dopaminergic neurons are the primary drivers of PD pathogenesis. While siRNA-mediated knockdown of α-synuclein can offer some protection to dopaminergic neurons, its clinical utility is hampered by low cellular uptake, off-target effects, and transient activity. These drawbacks underscore the urgent need for novel strategies that can efficiently and specifically degrade α-synuclein to delay or even halt PD progression. Our prior work identified tat-βsyn-deg (PDR-001), a three-segment peptide that selectively targets α-synuclein. When packaged into AAV9 capsids and delivered via bilateral stereotaxic injection into the subthalamic nucleus, this peptide effectively reduces α-synuclein within the target region. Pre-clinical studies in both human-α-synuclein-expressing mice and non-human primate models of PD have demonstrated robust α-synuclein clearance and marked improvements in motor deficits (see Research Foundation). The present project will advance PDR-001 into first-in-human studies to evaluate safety and explore preliminary efficacy. Unlike conventional symptomatic therapies, this approach targets the root cause of PD, setting the stage for disease-modifying treatment. Successful translation would establish a new therapeutic paradigm capable of slowing or preventing PD progression.

Interventions

• Drug PDR001
  This drug was packaged into AAV9 capsids and delivered via bilateral stereotaxic injection into the subthalamic nucleus

Primary outcome measures

• PDR-001 treatment-related adverse events as assessed by CTCAE v5.0 [Time frame: From enrollment to the end of treatment at 52 weeks]
• Titer levels of capsid neutralizing antibodies and binding antibodies against recombinant adeno-associated virus (rAAV) in serum [Time frame: From enrollment to the end of treatment at 52 weeks]
• Titer of rAAV vectors in whole blood [Time frame: From enrollment to the end of treatment at 52 weeks]

Secondary outcome measures (8)

• Evaluation of the use of antiparkinsonian drugs will be assessed using the Levodopa Equivalent Daily Dose (LEDD) [Time frame: From enrollment to the end of treatment at 52 weeks]
• Treatment efficacy will be evaluated using the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) [Time frame: From enrollment to the end of treatment at 52 weeks]
• Treatment efficacy will be evaluated using the Patient Global Impression - Improvement scale (PGI-I) [Time frame: From enrollment to the end of treatment at 52 weeks]
• Treatment efficacy will be evaluated using the Clinical Global Impression - Improvement scale (CGI-I) [Time frame: From enrollment to the end of treatment at 52 weeks]
• Treatment efficacy will be evaluated using the Mini-Mental State Examination (MMSE) [Time frame: From enrollment to the end of treatment at 52 weeks]
• Treatment efficacy will be evaluated using the Hamilton Depression Rating Scale (HAM-D, 17-item version) [Time frame: From enrollment to the end of treatment at 52 weeks]
• Change in anxiety symptoms as measured by the Hamilton Anxiety Rating Scale (HAM-A) [Time frame: From enrollment to the end of treatment at 52 weeks]
• Change in sleep-related problems as measured by the Parkinson's Disease Sleep Scale-2 (PDSS-2) [Time frame: From enrollment to the end of treatment at 52 weeks]

Eligibility criteria

Inclusion criteria

To be eligible for inclusion in this clinical study, all of the following criteria must be met:

• Clinically confirmed diagnosis of primary PD (in accordance with the 2016 Chinese Diagnostic Criteria for Parkinson's Disease or the 2015 MDS Clinical Diagnostic Criteria for primary PD);
• Age 40-65 years (inclusive) at screening, either sex;
• Disease duration ≤ 5 years;
• Hoehn \& Yahr stage ≤ 2 in the "off" state.

Exclusion criteria

Exclusion criteria

• Atypical or secondary parkinsonian syndromes (e.g., Parkinson-plus syndromes, hereditary parkinsonism, drug-induced parkinsonism, etc.).
• Contra-indications to surgery, or any prior intracranial procedure such as deep-brain stimulation, pallidotomy, or other extrapyramidal surgery, or any other neurosurgical intervention deemed by the investigator to interfere with study participation.
• Previous neuroimaging revealing structural brain abnormalities, cerebral vascular malformations, intracranial tumors, risk of intracranial hemorrhage, traumatic brain injury, or other significant findings.
• Mini-Mental State Examination (MMSE) score < 24.
• Patient Health Questionnaire-9 (PHQ-9) score ≥ 16.
• Abnormal hepatic or renal function: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 × upper limit of normal (ULN), or serum creatinine (Cr) > 1.5 × ULN.
• Coagulation disorders or current use of anticoagulants.
• Positive screening for infectious diseases:

• Hepatitis B surface antigen (HBsAg) or Hepatitis B virus DNA (HBV-DNA) positive;
• Hepatitis C virus RNA (HCV-RNA) positive;
• Human immunodeficiency virus (HIV) positive;
• Positive syphilis serology.
• Currently receiving antiviral therapy for hepatitis B or C.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Ruijin hospital — Shanghai

Identifiers

NCT: NCT07157345 · V1.0/2025-07-06

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗