Intranasal Gene Delivery Using Cationic Liposomes: A Novel Treatment Strategy for Parkinson’s Disease

Student: Robin Ortiz
Department: Pharmaceutical Sciences
Advisor: Barbara Waszczak

Abstract

Glial cell line-derived neurotrophic factor (GDNF) has been shown to exert neuroprotective and neuroregenerative effects on substantia nigra (SN) dopamine neurons and has potential in the treatment of Parkinson’s disease. However, clinical use of GDNF has been limited by its inability to cross the blood-brain barrier thus restricting its use to invasive intracerebral infusions. Nanotechnology was used to develop a non-invasive, cationic liposomal system for nasal delivery of GDNF to the brain. The intranasal route of administration was selected because it bypasses the blood-brain barrier, avoids systemic absorption, and lessens associated peripheral side effects. GDNF cationic liposomes had particle sizes averaging 175 nm, surface charge of 25 mV, and 98% loading efficiencies. We administered the formulation intranasally to rats before surgically creating a lesion by administering 6-hydroxydopamine (6-OHDA) to mimic the cell death of Parkinson’s disease and we then performed immunohistochemistry. In comparison to control groups for PBS liposomes and GDNF in PBS, we seem to have observed a statistically significant protective effect with use of the GDNF liposomes against the neurotoxic 6-OHDA.

Parkinson’s disease (PD) is due to a loss of dopaminergic neurons in the A9 nigrostriatal pathway of the midbrain, which includes the substantia nigra. Recently, medical advances have been made in PD using Glial Cell Line-Derived Neurotrophic Factor which supports the growth of dopaminergic neurons. However, there is an obstacle of getting this potential cure for PD into the brain across the blood-brain-barrier. One approach is to use GDNF “gene therapy” as a potential PD treatment, but the question has been how to deliver the gene selectively to the brain. Mattia and I will both use intranasal administration of cationic liposomes. However, whereas Mattia will attempt to deliver GDNF protein to the brain, I will attempt to deliver the gene (cDNA) for GDNF.