Cell Based Nano Therapeutic for Drug Delivery in a Parkinson’s Mouse Model
Nicole Stone1, Myosotys Rodriguez Martinez2, Nazira El-Hage2
1Herbert Wertheim College of Medicine, 2Cellular and Molecular Medicine, Herbert Wertheim College of Medicine
Objective:
This project aims to develop a cell-based brain delivery tool and to measure the efficacy of the delivered drug in a Parkinson’s disease (PD) mouse model.
Background:
The blood-brain barrier (BBB) remains an obstacle to the routine use of systemically administered macromolecules for PD therapy. Here, we utilized extracellular vesicles (EVs) for the transport of a potent neurotrophic factor, Glial cell line-derived neurotrophic factor (GDNF), in a transgenic PD model, Parkin-Q311X(A) mice. GDNF has been shown to improve symptoms in a mouse model of PD when administered intranasally. Here, we also deciphered the potential mechanism of action of GDNF in aged-matched transgenic animals and wild-type counterparts through measurement of the expression of neuroinflammatory, autophagy, and senescence-related genes.
Design/Methods:
GDNF plasmid was transfected to macrophages. Extracellular vesicles were then isolated and purified. GDNF expression was quantified by Western blotting and subsequently analyzed for purity. Animals underwent intranasal injection with EV-GDNF or saline per their assigned treatment. Locomotor activity and rearing movements were evaluated with wire-hanging test, rotarod test and open-field test. Brain tissues were harvested at 16 months for histochemical and biochemical analysis.
Biochemical analysis of WT16-month, PD-Saline, and treated PD-GDNF tissues for the expression of senescence and autophagy-related genes was performed by PCR array.
Results:
The PD-GDNF mice exhibited significantly decreased inflammatory markers compared to PD-Saline mice and were the same or lower than WT16-month mice. Among the genes assessed were E2f1, which plays a role in cell cycle regulation, Egr1 and Igf1r, which promote neuroinflammation and dopaminergic neurodegeneration in PD, and Trp53, which activates autophagy.
Conclusions:
Our data demonstrated significant regulation of genes involved in the neuroinflammatory pathology of PD, suggesting potential involvement of the autophagy and senescence pathways in the observed therapeutic effects by GDNF. Future directions will be to confirm our results at the protein level with western blotting and ELISA.
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