Intranasal Delivery of GDNF-expressing Nanoparticles to the Brain: Toward a Gene Therapy Approach for Parkinsons Disease

Student: Brendan Harmon
Department: Pharmaceutical Sciences
Advisor: Barbara Waszczak

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that primarily destroys the A9 tract of dopamine neurons that project from the substantia nigra pars compacta (SNc) to the corpus striatum (made up of the caudate and putamen in humans). For dopamine neurons specifically, glial cell-derived neurotrophic factor (GDNF) has been shown to promote their survival and proliferation both in culture and in vivo. GDNF has even been shown to be neuroprotective and restorative in various animal models of PD and some human clinical trials. However, its delivery is far from clinically practical since its use involves invasive surgical routes directly to the brain. The purpose of the proposed research is to advance non-viral gene delivery systems to the CNS using a rarely-utilized route of administration, the intranasal pathway. Intranasal administration circumvents the blood‐brain barrier (BBB), providing a non‐invasive means of targeting large molecular weight substances to the brain. Focusing on a treatment for PD, we hope to combine the therapeutic potential of GDNF gene transfection with the non-invasive approach of intranasal delivery to the brain. Expression plasmids containing the reporter genes for enhanced green fluorescent protein (EGFP) and luciferase will be evaluated using lipoplex and poly-lysine nanoparticle formulations. The formulation found superior for brain transfection will be carried forward and used for pGDNF delivery; the efficacy of which will be evaluated in a 6-hydroxydopamine (6-OHDA)-lesioned rat, a common animal model for PD.