Advancing Parkinson's Prevention: Brain-Specific Lipopolyplex Delivery of the GDNF as a Neuroprotective Gene Therapy.
Advancing Parkinson's Prevention: Brain-Specific Lipopolyplex Delivery of the GDNF as a Neuroprotective Gene Therapy.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
CN · Author affiliation · country only
Ministry of Education, Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, University of Macau, Macau, SAR 999078, China.Location evidence
Shenzhen, CN · Author affiliation
Research Center for Primate Neuromodulation and Neuroimaging, Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.Location evidence
HK · Author affiliation · country only
Shenzhen Technological Research Center for Primate Translational Medicine, Shenzhen Key Laboratory for Molecular Biology of Neural Development, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.Location evidence
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Original abstract
Parkinson's disease (PD) is characterized by progressive dopaminergic neuron loss. Although the glial cell line-derived neurotrophic factor (GDNF) offers therapeutic promise, its clinical translation is hampered by challenges related to delivery methods and the timing of intervention. Here, we developed a brain-targeted lipopolyplex (BAGLPP) for systemic GDNF gene delivery. BAGLPP incorporates an RVG29 peptide-modified lipid shell for blood-brain barrier crossing and a polyethylenimine-condensed AAV plasmid core for efficient transfection. Following intravenous administration, BAGLPP demonstrated superior brain accumulation and expression in PD-relevant regions. In a cellular PD model, BAGLPP pretreatment reduced apoptosis, oxidative stress, and pathological α-synuclein (pS129) accumulation. In MPTP-induced mice, prophylactic BAGLPP treatment established sustained GDNF expression (maintaining levels 3.7-fold higher than controls at 8 weeks postlesion), which activated the PI3K/Akt pro-survival pathway, suppressed pro-apoptotic Bax, and attenuated neuroinflammation. This multifaceted protection preserved dopaminergic neurons and striatal dopamine and improved motor function without significant systemic toxicity. Our findings establish BAGLPP as a durable, nonviral gene therapy platform with strong potential for preventing PD progression.