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.