Evaluation of intranasal gene delivery by a lipoplex formulation

• Online Access: http://hdl.handle.net/2047/d20002584

Parkinson's disease (PD) is a debilitating neurodegenerative disorder that results in the progressive loss of dopaminergic (DA) neurons from a midbrain nucleus known as the substantia nigra. Loss of these neurons, which project to the dorsal striatum, an area involved in initiation of voluntary movement, causes motor deficits that include resting tremor, bradykinesia, and rigidity. Available treatment options seek to replace dopamine, directly stimulate striatal neurons, or extend the lifetime of remaining dopamine but such treatments do not prevent disease progression and all are subject to decreasing efficacy over the course of long-term use. Glial cell-line derived neurotrophic factor (GDNF) is a neuroprotective protein that has emerged as a therapeutic agent with the potential to halt the loss of dopaminergic neurons caused by PD. However, GDNF must reach structures deep within the brain to be effective, a problem that currently necessitates invasive surgery to deliver the protein. Gene therapy is one method for achieving long-term expression of therapeutic proteins, but available methods for delivering genes rely on viral vectors that can be both immuno- and oncogenic. With this study, we sought to assess a non-invasive, non-viral method for delivering therapeutic genes to the rat brain. Lipoplex plasmid DNA vectors encoding EGFP were administered intranasally to bypass the blood brain barrier. Analysis via fluorescence microscopy and sandwich ELISA revealed no significant differences in the level or apparent EGFP between animals that received empty liposomes, naked pEGFP, and pEGFP lipoplexes. However, several confounding variables were encountered and further study is warranted.