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

Summary

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.

Eligibility

Inclusion Criteria:

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

1. 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);
2. Age 40-65 years (inclusive) at screening, either sex;
3. Disease duration ≤ 5 years;
4. Hoehn \& Yahr stage ≤ 2 in the "off" state.

Exclusion Criteria:

Exclusion Criteria

1. Atypical or secondary parkinsonian syndromes (e.g., Parkinson-plus syndromes, hereditary parkinsonism, drug-induced parkinsonism, etc.).
2. 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.
3. Previous neuroimaging revealing structural brain abnormalities, cerebral vascular malformations, intracranial tumors, risk of intracranial hemorrhage, traumatic brain injury, or other significant findings.
4. Mini-Mental State Examination (MMSE) score \< 24.
5. Patient Health Questionnaire-9 (PHQ-9) score ≥ 16.
6. 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.
7. Coagulation disorders or current use of anticoagulants.
8. 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.
9. Currently receiving antiviral therapy for hepatitis B or C.

Conditions2

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