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Delivery of GDNF to the Brain by Novel Nanovesicles for the Treatment of Parkinson’s Disease (P6.082)

2014; Lippincott Williams & Wilkins; Volume: 82; Issue: 10_supplement Linguagem: Inglês

10.1212/wnl.82.10_supplement.p6.082

1526-632X

Eliahu Heldman, Sarina Grinberg, Charles Linder, Mary Popov, Irwin Hollander,

Supramolecular Self-Assembly in Materials

OBJECTIVE: To demonstrate delivery of GDNF to brain regions affected in Parkinson's (PD) by novel nano-vesicles (V-SmartTM) targeted to dopaminergic neurons for treatment of PD. BACKGROUND: Neurotrophins like GDNF have good potential as therapeutic agents in PD. However, neurotrophins do not penetrate the BBB and a targeted delivery system is needed to derive their therapeutic potential. Here we describe optimized V-SmartTM vesicles (based on our nano-vesicles shown to cross the BBB and deliver proteins and siRNA) capable of delivering GDNF to the striatum and the substantia nigra -- brain regions affected in PD. DESIGN/METHODS: Nano-vesicles were formed from synthetic bolaamphiphiles containing: acetylcholine head groups that enable release from the vesicles upon exposure to AChE; targeting ligand that enables targeting to dopaminergic neurons; and chitosan moieties that enable penetration through the BBB. Carboxyfluorescein-loaded vesicles were added to cultured cells, then studied by FACS. GDNF-loaded vesicles were administered intravenously to mice, which were then perfused with PBS at various times after vesicle administration, brains removed, homogenized or sectioned for histology, and brain GDNF determined quantitatively by ELISA and localized by histofluorescence. RESULTS: Vesicles decorated with targeting ligand bind to cultured cells that express receptor significantly more than naked vesicles do, whereas no difference is found between naked and decorated vesicles in cultured cells that do not express receptor, suggesting that in vivo specific targeting to dopaminergic cells would occur. GDNF, encapsulated in vesicles decorated with targeting ligand, was administered intravenously to mice and found in significant amounts in the brain with preferential localization in the striatum and substantia nigra -- brain regions rich in dopaminergic cells. CONCLUSIONS: V-SmartTM vesicles, optimized for targeted delivery of GDNF, successfully delivered GDNF into areas of the brain affected by Parkinson's and, thus, show great potential for PD therapy. Efficacy studies are currently being conducted in PD animal models. Study Supported by: The Michael J. Fox Foundation